Prussian Blue

DRAFT for comment - not for distribution
1
2
3
4 IPCS EVALUATION OF ANTIDOTES FOR POISONING BY
5 METALS AND METALLOIDS
6
7
8
9 PRUSSIAN BLUE
10
11 Potassium ferric (III) hexacyanoferrate (II) (colloidal soluble Prussian Blue,

12 KFe[Fe(CN)6) and ferric (III) hexacyanoferrate (II) (insoluble Prussian Blue, Fe4
13 [Fe(CN)6]3)
14
15
16
17
18 Initial draft (1994):
19 A.N.P. van Heijst (National Poisons Control Centre, Utrecht, The Netherlands), A. von Dijk
20 (Apotheek, Academisch Ziekenhuis, Utrecht, The Netherlands) & J. Ruprecht (Heyl
21 Pharmaceuticals, Berlin, Germany)
22
23 Update (2009):
24 M McParland and P Dargan (Medical Toxicology Information Services, Guy's & St Thomas'
25 NHS Foundation Trust, London, UK)
26
27
28
29
30
31
1
32
33 1. Introduction .................................................................................................................. 3
34 2. Name and Chemical Formula of Antidote.................................................................... 3
35 3. Physico-chemical Properties ........................................................................................ 4
36 4. Synthesis and Pharmaceutical Formulation ................................................................. 5
37 5. Analytical Methods ...................................................................................................... 7
38 6. Shelf-life ....................................................................................................................... 9
39 7. General Properties ........................................................................................................ 9
40 8. In Vitro Studies .......................................................................................................... 11
41 9. Animal Studies ........................................................................................................... 12
42 10. Volunteer Studies ....................................................................................................... 21
43 11. Clinical Studies Clinical Trials ............................................................................... 23
44 12. Clinical Studies - Case Reports .................................................................................. 23
45 13. Summary of Evaluation.............................................................................................. 36
46 14. Model Information Sheet............................................................................................ 40
47 15. References .................................................................................................................. 42
48 16. Author(s) Name, Address........................................................................................... 51
49 17. Additional Information............................................................................................... 51
50 Results of Cochrane Library Search 4th November 2009 ................................................... 52
51 Table 3: Summary of evidence of use of Prussian blue in metal poisoning ......................... 1
52 Table 4: Summarized case reports of thallium poisoning..................................................... 6
2
53 1. Introduction
54
55 Prussian blue was first prepared in 1704 and used principally as an inorganic pigment
56 (Faustino, 2008). Work in the 1960s investigated the use of Prussian blue as an antidote for
57 thallium poisoning and a decorporation agent for radiocaesium (caesium-134 and caesium-
58 137). From the 1970s Prussian blue was recommended as an antidote in thallium
59 intoxication and it is now routinely used for this purpose. Further studies into its use for
60 increasing the elimination rate of radiocaesium were undertaken following the Chernobyl
61 nuclear reactor accident in 1986 but it was only after Goinia incident in 1987 that it was
62 used in the management of a large scale radiation accident (Faustino, 2008).
63
64 There are two forms of Prussian blue, ferric (III) hexacyanoferrate (II) (insoluble Prussian
65 blue) and potassium ferric (III) hexacyanoferrate (II) (soluble or colloidal Prussian blue). It
66 is essential to be specific about which form of Prussian blue has been used in future
67 publications. The different forms should be identified by citing the correct chemical name
68 and/or chemical formula and/or the physical nature (insoluble or colloidal soluble).
69
70 Prussian blue is given orally and acts via ion exchange, adsorption and mechanical trapping
71 to bind thallium and caesium within its crystal lattice, interrupting their enterohepatic
72 circulation, enhancing faecal elimination and reducing body burden.
73
74 Insoluble Prussian blue is used to treat patients with known or suspected internal
75 contamination with radioactive caesium, radioactive thallium and non-radioactive thallium,
76 to increase their rates of elimination. Prussian blue can reduce the biological half-life of
77 radiocaesium by about a third. There is one report where Prussian blue has been used for the
78 treatment of non radioactive caesium toxicity (Thurgur et al., 2006) and rubidium has also
79 been shown to bind to Prussian blue (Hoffman, 2006).
80
81 Prussian blue is well tolerated but can result in constipation. It is essential to treat
82 constipation as it will decrease elimination of thallium and caesium and some authors advise
83 administration of Prussian Blue with laxatives to prevent constipation.
84
85
86 2. Name and Chemical Formula of Antidote

87
88 There are two forms of Prussian blue, ferric (III) hexacyanoferrate (II) (insoluble Prussian
89 blue) and potassium ferric (III) hexacyanoferrate (II) (soluble or colloidal Prussian blue).
90 Synonyms which apply to both compounds include Berlin blue, Milori Blue, Chinese blue,
91 Hamburg blue, mineral blue, Pigment blue 27 and Paris blue.
92
Potassium ferric (III) Ferric (III) hexacyanoferrate (II)
hexacyanoferrate (II)
Synonyms colloidal soluble Prussian blue, insoluble Prussian blue, IPB, ferric
SPB, potassium ferric ferrocyanide, Iron (III) ferrocyanide,
ferrocyanide, Ferrotsin, Ferrocin,
Ferrihexacyanoferrate, ferric
cyanoferrate (II)
Molecular formula KFe[Fe(CN)6] Fe4[Fe(CN)6]3
Molecular weight 306.9 859.3
3
Potassium ferric (III) Ferric (III) hexacyanoferrate (II)

hexacyanoferrate (II)
CAS Registry No 12240-15-2 14038-43-8
Colour Index No. 77520 77510
RTECS number LJ8200000
Structural diagram
(ChemIDplus Lite)
93
94
95
96
97 Prussian blue is a non-stoichiometric compound and the chemical formulae for both forms
98 shown above are therefore idealized. Additionally all precipitates of insoluble Prussian blue
99 contain nonstoichiometric amounts of potassium, protons and water (Dvok, 1971; Nielsen
100 et al., 1987; Nielsen et al, 1988b). The water is partially adsorbed at the large surface of this
101 pigment, partially distributed in the cavities of the crystal lattice (zeolithical water) and
102 partially coordinatively bound (Ludi, 1988). Colloidal soluble Prussian blue may
103 additionally contain nonstoichiometric amounts of cations (H+, alkali metal ions) and anions
104 (Cl-, OH) and water (Bozorgzadeh, 1971; Dvok, 1970; Dvok, 1971).
105
106 Insoluble Prussian blue is the only commercially available pharmaceutical preparation
107 however in the literature there is confusion over the two available forms of Prussian blue and
108 inconsistencies in the nomenclature of Prussian blue (Hoffman, 2006). For example, some
109 authors who used the commercially available Prussian blue Antidotum Thallii-Heyl
110 containing insoluble ferric hexacyanoferrate have incorrectly described the chemical formula
111 as KFe[Fe(CN)6] (Franke et al., 1979) or named the compound as potassium ferric
112 ferrocyanide (Spoerke et al., 1986). In another report both formulae are used KFe[Fe(CN)6]
113 and Fe4[Fe(CN)6]3 for Antidotum Thallii-Heyl (Trenkwalder et al., 1984). In other cases
114 the drug Antidotum Thallii-Heyl is described as "colloidal soluble Prussian blue" (Jax et
115 al., 1973; Kemper, 1979; Gansser, 1982; Forth, 1986) or potassium ferric (III)
116 hexacyanoferrate (II) is described as insoluble (Lehmann & Favari, 1984). As a result it is
117 often very difficult or impossible to determine which form of Prussian blue was used.
118
119 Where possible, the two forms of Prussian blue are identified here as soluble Prussian blue
120 and insoluble Prussian blue.
121
122 3. Physico-chemical Properties

123
4
124 Melting point: Not available.

125
126 Solubility: Potassium ferric (III) hexacyanoferrate (II) is colloidally soluble in water, ferric
127 (III) hexacyanoferrate (II) is insoluble in water and diluted acids (solubility product
128 =10-40, i.e. practically insoluble) (Ludi, 1988). 59Fe-labelled measurements resulted
129 in a solubility of 1.1 mol/L for potassium ferric (III) hexacyanoferrate (II) and 0.7
130 mol/L for ferric (III) hexacyanoferrate (II) (Dvok, 1970).
131
132 Optical properties: Not available.
133
134 pH: Not available.
135
136 pKa: Not available.
137
138 Stability in light: Prussian blue should be stored in tightly closed containers protected from
139 light.
140
141 Thermal stability: Not available.
142
143 Refractive index: Not available.
144
145 Specific gravity: 1.8
146
147 Loss of weight on drying: Potassium ferric (III) hexacyanoferrate (II) 6-15% loss of weight
148 on drying at 150C. Ferric (III) hexacyanoferrate (II) 28-34% loss of weight on
149 drying at 105C.
150
151 Excipients and pharmaceutical aids: In both pharmaceutical preparations, Antidotum Thallii-
152 Heyl and Radiogardase-Cs, ferric (III) hexacyanoferrate (II) is provided as 500mg
153 of Prussian blue powder in gelatine capsules with 0-38mg of microcrystalline
154 cellulose. The powder may vary in coarseness and colour shade (Heyl, 2004).
155
156 Pharmaceutical incompatibilities: None known.
157
158 Binding to some therapeutic drugs and essential nutrients is possible. Insoluble Prussian blue
159 may bind electrolytes in the gastrointestinal tract. Hypokalaemia (potassium 2.5-2.9)
160 was reported in 3 of 42 patients (7%) treated with insoluble Prussian blue (Heyl,
161 2004; Thompson & Callen, 2004; Thompson & Church, 2001). There are some
162 anecdotal reports of Prussian blue decreasing the bioavailability of oral tetracycline
163 and the serum levels and, or clinical response to critical orally administered products
164 should be monitored (Heyl, 2004).
165
166 4. Synthesis and Pharmaceutical Formulation

167
168 4.1 Routes of Synthesis
169 Both substances can be synthesized according to the method of Dvok (1969). The basic
170 chemicals needed are the same for both substances. However, the salt ultimately formed will
171 depend on the ratio of the raw materials and the way in which they are added to each other.
172
5
173 FeCl3 + K4[Fe(CN)6] ------ > KFe[Fe(CN)6] + 3 KCl

174
175 4 FeCl3 + 3 K4[Fe(CN)6]----- > Fe4[Fe(CN)6]3 + 12 KC1
176
177 Raw materials:
178 Ferric chloride (FeCl3) and potassium ferrocyanide (K4[Fe(CN)6])
179
180 Water suitable for injection or of comparable quality (i.e. water with cation and anion
181 concentrations equal or less than water for injection).
182
183 Synthesis:
184 (a) Basic solutions
185
186 Dissolve appropriate amounts of FeCl3 and K4[Fe(CN)6] in water so that the molar ratio of
187 the two solutions is 2.0. This means that when a 0.2 M ferric chloride solution has been
188 prepared, the molarity of the K4[Fe(CN)6] solution should be 0.1 M.
189
190 (b1) Potassium ferric (III) hexacyanoferrate (II)
191
192 It is essential that the final stoichiometric ratio Fe3+/ [Fe(CN)6 ]4- in the reaction
193 mixture equals 0.33. When 1 litre of 0.2 M ferric chloride solution is used, then
194 (1000 x 0.2)/(0.33 x 0.1) 6060 ml of a 0.1 M (Fe(CN)6]4- solution is necessary. The
195 quantity of [Fe (CN)6]4- is added drop wise to the ferric chloride solution whilst
196 stirring vigorously. Centrifuge at 120000g after one hour standing. Wash the
197 precipitate three times with water and centrifuge after each washing step. Dry the
198 precipitate obtained after the last washing step at 105 oC until the weight remains
199 constant.
200
201 To remove possible low molecular impurities some authors have dialysed the
202 colloidal soluble Prussian blue exhaustively against water (Mller et al., 1974;
203 Nielsen et al., 1987; Nielsen et al., 1988a; Nielsen et al., 1988b).
204
205 (b2) Ferric (III) hexacyanoferrate (II)
206
207 It is essential that the final stoichiometric ratio Fe3+/ [Fe(CN)6]4- in the reaction
208 mixture equals 1.33. When 1 litre of 0.2 M ferric chloride solution is used, then
209 (1000 x 0.2)/(1.33 x 0.1) 1504 ml of a 0.1 M [Fe(CN)6]4- solution is necessary. The
210 quantity of [Fe(CN)6]4- is added drop wise to the ferric chloride solution whilst
211 stirring vigorously. Filter standing for one hour. Wash the precipitate and filter
212 three times after each washing step. Dry the precipitate obtained after the last
213 washing step at 105 oC until weight remains constant. The drying process influences
214 the efficacy of the substance (Nigrovi et al., 1966). The effectiveness of Radiogar-
215 dase-Cs in binding caesium was higher than that of the ferric (III) hexacyanoferrate
216 (II) synthesized by the authors (Nielsen et al., 1987). Among other things this can be
217 attributed to a special drying procedure.
218
219 After synthesis as described, and after one year's storage in tightly closed containers
220 at room temperature, neither substance showed any significant decomposition into
221 cyanide ion (Dvok, 1970). The effectiveness of ferric (III) hexacyanoferrate (II)
222 was not decreased after storage during one year (Nigrovi et al., 1966).
6
223
224 4.2 Manufacturing processes
225 Not known.
226
227 4.3 Presentation and formulation
228 Prussian blue is available as Radiogardase-Cs (Radiogardase in the United States of
229 America) and Antidotum Thallii-Heyl distributed by Heyl Chemisch-pharmazeutische
230 Fabrik GmbH, Berlin, Germany.
231
232 Both products are available in bottles of 30 hard gelatine capsules, each containing 0.5 g of
233 insoluble Prussian blue.
234
235 5. Analytical Methods

236
237 5.1 Quality control procedures for the antidote and/or its formulation
238
239 5.1.1 Test for the presence of colloidal Prussian blue:
240 A mixture of 10 g insoluble Prussian blue and 50 ml of distilled water is shaken and filtered
241 using a membrane filter. The filtrate should show no blue colouration (absence of colloidal
242 soluble Prussian blue).
243
244 5.1.2 Test for the presence of insoluble Prussian blue:
245 Shake 100 mg of colloidal soluble Prussian blue with 20 ml of water. An intensely dark blue
246 solution is obtained. Precipitation should not occur before a standing time of two days has
247 passed (test to exclude the insoluble form).
248
249 5.1.3 Test for the presence of hexacyanoferrate (II) and hexacyanoferrate (III):
250 10 g Prussian blue and 50 ml distilled water are shaken and filtered using a membrane filter.
251 The filtrate is then mixed with the hydrochloric acid salt of ferrous ammonium sulphate
252 ((NH4)2Fe (II)(SO4)2) or ferric ammonium sulphate ((NH4)Fe (III)(SO4)2). The absence of
253 blue colour indicates that K3[Fe (III)(CN)6] is less than 5 ppm and K4[Fe (II)(CN)6] is less
254 than 20 ppm respectively.
255
256 5.1.4 Test for iron content:
257 500 mg Prussian blue in 50 ml water are shaken and filtered. Compared with an iron
258 standard solution the iron content should be not more than 100 ppm.
259
260 5.1.5 Test for heavy metal content:
261 After digestion of Prussian blue with concentrated sulphuric acid the heavy metal content
262 (measured as lead) should be less than 50 ppm. Arsenic content must be less than 5 g/g.
263
264 5.1.6 Removal of oxalic acid:
265 Prussian blue may contain oxalic acid, originating from the manufacturing process. Shake 1
266 g of Prussian blue with 10 ml sodium acetate solution (Dutch Pharmacopoeia, 1966).
267 Centrifuge and filter the upper layer through a paper filter folded three times. Add to 5 ml
268 filtrate 1 ml of calcium acetate solution (Dutch Pharmacopoeia, 1966). No precipitate of
269 calcium oxalate should occur after 24 hours. Since no oxalic acid is used in the above speci-
270 fied synthesis, quality control for this acid may be omitted provided that the raw materials do
271 not contain it. The commercially available pharmaceuticals Prussian blue in Antidotum
7
272 Thallii-Heyl and Radiogardase-Cs do not contain oxalic acid.

273
274 5.2 Methods for identification of the antidote
275 Detection of ferric (III) and hexacyanoferrate (II) ions: 500 mg of Prussian blue is heated in
276 5 ml of 3M potassium hydroxide resulting in decomposition to brown, flocculent ferric
277 hydroxide. After deposition the supernatant fluid appears yellow (K4[Fe(CN)6]). After fil-
278 tration, 2 ml of the fluid is acidified with concentrated hydrochloric acid and mixed with a
279 FeCl3 solution and this will result in blue colouration or formation of a blue precipitate.
280
281 5.3 Methods for analysis of the antidote in biological samples
282 Not applicable.
283
284 N.B. It is often stated that Prussian blue is not absorbed to any significant extent however
285 anecdotal reports suggest prolonged therapy results in a blue discolouration of sweat and
286 tears suggesting some absorption.
287
288 5.4 Analysis of the toxic agents in biological samples
289
290 5.4.1 Analysis of thallium in urine, plasma and erythrocytes
291 Thallium can be measured by spectrophotometry, flame atomic absorption
292 spectrophotometry (AAS) and electrothermal atomic absorption spectrophotometry
293 (ETAAS) (Moffat et al, 2004).
294
295 5.4.1.1 Spectrophotometry
296 A spectrophotometric method was described by de Wolff and Lenstra (1964). It involves the
297 determination of thallium at 550nb using rhodamine 'B' or brilliant green and can be used on
298 urine and on blood diluted with water. The limit of quantification is approximately 50g/L
299 (Moffat et al, 2004). This method is described in the Thallium Poisons Information
300 Monograph (IPCS, 1990).
301
302 Another spectrophotometric method is described by Flanagan et al (1995). In this method a
303 pink-red colour indicates the presence of thallium at concentrations of 1mg/l or more. A
304 calibration graph of absorbance against thallium concentration in standard samples can be
305 used to measure the thallium concentration more precisely. The limit of sensitivity is 0.1
306 mg/L.
307
308 5.4.1.2 Atomic Absorption Spectrophotometry
309 Flame AAS can be used to measure thallium in plasma, blood or urine by extracting it as a
310 pyrrolidine dithiocarbamate complex in an organic solvent (de Groot et al, 1985). The lowest
311 quantifiable concentration is at least 0.2 mg/l and depends on the atomic absorption
312 spectrophotometer used. Linearity is up to 5 mg/l. Higher concentrations can be measured
313 by diluting the sample under investigation with blank sample. This method is described in
314 the Thallium Poisons Information Monograph (IPCS, 1990).
315
316 ETAAS has been used for monitoring occupational exposure and has a limit of detection of
317 less than 1 g/L (Moffat et al, 2004).
318
319
320 5.4.2 Analysis of caesium in biological samples
321 Caesium-134 and caesium-137 decay by emitting beta particles and these nuclides are
8
322 detected using gamma spectrometry.

323
324 Specialist advice is essential for dose assessment following a radiation accident as this assists in
325 determining appropriate management and the expected clinical course. Radioactivity
326 measurements of the wound (if applicable), skin or chest (following inhalation), nasal swabs,
327 urine and faeces are also used to assess dose. In many cases the victim is not wearing a
328 dosimeter (and this only measures external exposure not the internal dose). In addition the
329 standard models for calculating intake from routine occupational exposures may not be
330 applicable and individual-specific models may have to be developed and applied for internal
331 dose calculations (Toohey, 2003).
332
333 A quantitative baseline of the internal contamination of radiocaesium should be obtained by
334 appropriate whole body counting and/or by bioassay, or faeces/urine sample whenever
335 possible to obtain the following type of information to establish an elimination curve:
336 Estimated internalised radiation contamination of caesium, and
337 Rate of measured elimination of radiation in the faeces (Heyl, 2004).
338
339
340 6. Shelf-life
341
342 The pharmaceutical products of Prussian blue should be stored in the dark at 25 0C;
343 occasional variations of temperature within the range 15 to 30 0C are permitted (Heyl, 2004).
344 For the pharmaceutical preparations Antidotum Thallii-Heyl and Radiogardase-Cs the
345 shelf-life is given as five years.
346
347 7. General Properties

348
349 Orally administered Prussian blue binds thallium or caesium in the gut and increases the
350 concentration gradient, enhancing elimination by gut dialysis. Thallium (Forth & Henning,
351 1979) and caesium (Nigrovi, 1965) also undergo enterohepatic circulation and Prussian
352 blue interrupts their reabsorption from the gastrointestinal tract thereby increasing faecal
353 excretion. Prussian blue therefore reduces the biological half-life of caesium and thallium.
354
355 The mechanism of caesium and thallium adsorption by hexacyanoferrates is believed to
356 involve chemical ion exchange whereby nonstoichiometric and stoichiometric cations of the
357 drug are exchanged by thallium or caesium ions. The affinity of Prussian blue increases as
358 the ionic radius of the cation increases, so Prussian blue preferentially binds caesium (ionic
359 radius 0.169 nm) and thallium (0.147 nm) over potassium (0.133 nm) and sodium (0.116
360 nm) (Forth, 1983; Nielsen et al., 1987). An influence of Prussian blue on potassium and
361 sodium levels is therefore not expected (Nigrovi et al., 1966). Rubidium (ionic radius
362 0.148) has also been shown to bind to Prussian blue (Hoffman, 2006).
363
364 Evidence is provided by a number of experimental studies. After binding of thallium to
365 colloidal soluble and insoluble Prussian blue, the content of potassium and hydrogen ions
366 was reduced (Dvok, 1970). 40K labelled colloidal Prussian blue showed no radioactivity
367 after mixing with thallium. The pH value was decreased, indicating release of H+ ions
368 (Dvok, 1971). In in vitro experiments insoluble Prussian blue bound more caesium than
369 potassium, and hydrogen and iron ions were released.
9
370
371 There may be other mechanisms in addition to ion exchange. Nielsen et al. (1987) found that
372 colloidal soluble Prussian blue released more potassium than it adsorbed caesium,
373 suggesting that an additional, physical adsorption on its large surface, possibly interacting
374 with water, may be involved (Ludi, 1983; Richmond, 1968). Yang et al (2008) found that
375 the binding capacity of insoluble Prussian blue for thallium decreased as the water content of
376 Prussian blue was decreased. Forms of Prussian blue with a smaller crystal size, and
377 therefore a larger surface area, have a higher adsorptive capacity and antidotal efficacy for
378 thallium (Kravzov et al., 1993; Yang et al, 2008).
379
380 Non-dialyzed colloidal soluble Prussian blue initially proved to combine with thallium much
381 more effectively than ferric (III) hexacyanoferrate (II) in vitro as well as in vivo (Dvok,
382 1969; Dvok, 1970; Kamerbeek et al., 1971). This greater binding was not only the result
383 of the larger surface area of the colloidal soluble preparations (Dvok, 1970), but also
384 because of the larger amount of extra-stoichiometric potassium in these preparations
385 (Dvok, 1971). The sodium salt-derived preparation did not meet these requirements
386 (Rauws et al., 1979), and subtle differences in the dimensions of the crystal lattice might also
387 play a role (Keggin & Miles, 1936; Kravzov et al, 1993).
388
389 Colloidal soluble Prussian blue may, however, present problems. The production of a
390 standard colloidal soluble Prussian blue was found to be difficult resulting in a different
391 toxicity of the different preparations (Dvok et al., 1971). Long-term treatment of rats with
392 non-dialysed colloidal soluble Prussian blue resulted in actual caesium retention in the body
393 in treated rats compared to control animals (Bozorgzadh & Catsch, 1972; Mller et al.,
394 1974). Dresow et al., (1993) investigated the effect of soluble and insoluble Prussian blue in
395 rats, pigs and humans and concluded that for medical use in man, a separation of the low
396 molecular weight compounds from crude commercial preparations is recommended.
397
398 Following the introduction of colloidal potassium ferric (III) hexacyanoferrate (II) as an
399 antidote for thallium poisoning in 1970 (Kamerbeek, 1971; Kamerbeek et al., 1971), the
400 results of treatment with potassium ferric (III) hexacyanoferrate (II) as well as with ferric
401 (III) hexacyanoferrate (II) in patients with severe thallium poisoning published in the
402 literature have been associated with a favourable outcome, particularly when it is used early.
403 Treatment with Prussian blue in patients with thallotoxicosis can be life-saving but it does
404 not improve all the clinical signs, such as neurological signs or alopecia, particularly in late-
405 presenting patients.
406
407 Thompson & Callen (2004) reviewed the English language literature concerning the efficacy
408 of soluble and insoluble Prussian blue and its use as a therapeutic agent in radiocaesium and
409 thallium poisoning. They noted that most of the evidence describing the efficacy of Prussian
410 blue for radiocaesium poisoning is based on the use of the insoluble form, whilst similar
411 evidence for thallium poisoning involves the use of the soluble form. They concluded that
412 while there is sufficient evidence that the insoluble form of Prussian blue is effective in
413 radiocaesium poisoning, there is a lack of analogous data supporting its use in thallium
414 poisoning. The authors acknowledged that further research is needed to determine the
415 significance of any differences between the two forms of Prussian blue and whether their
416 physicochemical differences have any effect on outcomes in human poisoning is currently
417 unknown. However, the commercial products in current use are formulated with the
418 insoluble form of Prussian blue and most data collated from future use is likely to refer to
419 this form only.
10
420
421 8. In Vitro Studies

422
423 8.1 In vitro binding of caesium
424 Various in vitro studies have shown that Prussian blue binds caesium (Bozorgzadh, 1971;
425 Nielsen et al., 1987; Verzijl et al., 1992; Faustino et al., 2008).
426
427 In vitro binding of caesium to insoluble Prussian blue is affected by pH, exposure time,
428 storage temperature (affecting moisture content) and particle size. The lowest caesium
429 binding was at pH 1.0 and 2.0 and the highest at pH 7.5. Dry storage conditions results in
430 loss of moisture from Prussian blue which causes a negative effect on caesium binding
431 capacity. There is batch to batch variation in particle size and variation in binding capacity.
432 At 1, 4 and 24 hours it was determined that caesium binding increases as particle size
433 decreases. The maximum caesium binding capacity of insoluble Prussian blue was
434 approximately 715 mg/g (Faustino et al., 2008).
435
436 In a study comparing the binding capacity of soluble and insoluble Prussian blue, the
437 binding of caesium-137 was greater with insoluble Prussian blue (Radiogardase-Cs) and
438 was pH-dependent for both formulations. The maximum binding capacities for insoluble
439 Prussian blue were 87 mg/kg at pH 1.0, 194 mg/g at pH 6.5, and 238 mg/g at pH 7.5. For
440 soluble Prussian blue the maximum binding capacities were 48 at pH 1.0, 73 mg/g at pH 6.5,
441 and 78 mg/g at pH 7.5 (Verzijl et al., 1992).
442
443 Nielsen et al. (1987) investigated caesium binding by various hexacyanoferrate compounds
444 (iron, copper, cobalt, nickel, zinc, manganese) at pH 1.2 and 6.8. All the compounds bound
445 caesium; potassium copper hexacyanoferrate (II) and potassium zinc hexacyanoferrate (II)
446 were the most efficient at pH 1.2 and 6.8. These compounds had twice the binding capacity
447 of soluble and insoluble Prussian blue. These authors also demonstrated that whey
448 contaminated with caesium-134 and caesium-137 was almost completely decontaminated by
449 dialysing a whey suspension against a buffer solution containing insoluble Prussian blue.
450 The whey had been produced from the milk of South German cows contaminated in the
451 summer of 1986 following the Chernobyl accident.
452
453 8.2 In vitro binding of thallium
454 In vitro studies have demonstrated that thallium binds to both soluble (Dvok, 1970;
455 Kamerbeek et al., 1971; Krazov et al., 1993) and insoluble Prussian blue (Dvok, 1970;
456 Yang et al., 2008). The adsorption is rapid: after 10 minutes all thallium was bound (Dvok
457 et al., 1971). The effectiveness of soluble Prussian blue (as measured by mg of thallium/mg
458 Prussian blue or % adsorbed) was higher than that of insoluble Prussian blue (Dvok, 1970;
459 Kamerbeek et al., 1971). In vitro, thallium binds more strongly to Prussian blue than to
460 activated charcoal (Kamerbeek et al., 1971).
461
462 As with caesium, the thallium binding capacity of Prussian blue is affected by pH, exposure
463 time, storage temperature (affecting moisture content) and particle size. The adsorption of
464 thallium on Prussian blue depended on the pH-value of the solution and a maximal
465 adsorption could be detected at a neutral or slightly alkaline pH (Dvok, 1970). In the in
466 vitro study by Yang et al. (2008) the maximum thallium binding capacity of insoluble
467 Prussian blue was approximately 1400 mg/g at pH 7.5 after 24 hours. The lowest binding
468 occurred at pH 1.0 at 1 hour and thereafter, binding increased as pH increased (determined
11
469 up to pH 7.5). The binding constant was higher for fully hydrated Prussian blue compared to
470 Prussian blue which had been dried for 24 hours and the smaller the particle size the higher
471 the binding constant.
472
473 An in vitro study examined the adsorption of thallium-201 by insoluble Prussian blue to
474 investigate the use of Prussian blue in reducing the radiation burden in thallium-201
475 myocardial scintigraphy. The maximum adsorption peaked at approximately 30 minutes
476 irrespective of the concentration (1, 10 or 100 mg or Prussian blue in 5 mL of water). It
477 reached a plateau at 30 to 60 minutes with no further increase in adsorption of thallium until
478 4 hours. The rate of absorption was constant for up to 1 hour but slowed down thereafter.
479 Thallium-201 removal increased from 46 to 95% when the pH was increased from 2.0 to 8.0.
480 In the most favourable conditions the maximal adsorption capacity was 5000 MBq of
481 thallium-201/g of Prussian blue and maximal adsorption occurred at 30 minutes (Bhardwaj
482 et al., 2006).
483
484
485 9. Animal Studies

486
487 9.1 Pharmacodynamics
488
489 9.1.1 Caesium
490 A number of animal studies have examined the impact of Prussian blue on the absorption of
491 caesium, its effect on the enhancement of excretion (or reduced retention) of caesium and
492 the impact of these actions on final outcomes.
493
494 9.1.1.1 Prevention of absorption/uptake from gut
495 Administration of a single dose of radiocaesium and concomitant oral dosing of Prussian
496 blue resulted in reduction of caesium uptake from the gastrointestinal tract (Brenot &
497 Rinaldi, 1967; Dresow et al., 1990, 1993; Giese & Hantzch, 1970; Nielsen et al., 1988b;
498 Nigrovi, 1963; Nigrovi, 1965). In piglets potassium ferric (III) hexacyanoferrate (II) and
499 ferric (III) hexacyanoferrate (II) reduced the caesium-134 uptake by more than 97%. The
500 diminution of the caesium-134 body burden depended on the dose of administered
501 hexacyanoferrate (II). The difference between the colloidal and insoluble Prussian blue
502 compounds in decreasing enteral absorption of caesium-134 was small (Nielsen et al.,
503 1988b).
504
505 If Prussian blue was given as late as 60 minutes after caesium-137 administration the enteral
506 caesium-137 absorption was also suppressed (Nigrovi, 1963). Autoradiography of rats
507 showed, that the radioactivity was limited to the gastrointestinal-tract (Brenot & Rinaldi,
508 1967).
509
510 In rats administered a composite treatment mixture containing calcium alginate, potassium
511 iodide and insoluble Prussian blue in their diet and exposed to various radionucleotides, the
512 Prussian blue, even as a component of the mixture, decreased the absorption of caesium into
513 the organism and reduced the whole-body retention (Kargacin & Kostial, 1985; Kostial et
514 al., 1980; Kostial et al., 1981; Kostial et al., 1983).
515
516 In a study in pigs the animals (82 kg) were fed twice daily with pellet food and 500 mL of
517 milk together with 200 g of radiocaesium-contaminated whey powder. Prior to each feeding
12
518 the pigs were given 0.5g, 1.5g or 2.5 g of soluble Prussian blue, insoluble Prussian blue or
519 ammonium iron hexacyanoferrate (II) (NH4Fe[Fe(CN)6]) in gelatine capsules. The animals
520 were slaughtered after 27 days of feeding. All compounds were found to be effective at
521 reducing caesium-134 and caesium-137 absorption. Administration of increasing quantities
522 of the compounds resulted in a dose-dependent reduction in the radioactivity of the tissues
523 tested. Soluble Prussian blue and ammonium iron hexacyanoferrate were most effective,
524 possibly due to more favourable distribution of colloidal soluble compounds in the
525 gastrointestinal tract (Dresow et al., 1993). Similarly, soluble Prussian blue and ammonium
526 iron hexacyanoferrate were most effective in rats (260 to 280 g) given 0.5 mg of Prussian
527 blue in water 2 minutes before 0.5 mL of water containing a tracer dose of caesium-134, by
528 gastric tube. There was almost complete blockade of radiocaesium absorption as judged by
529 urinary excretion and whole body retention measured 7 days after ingestion. Insoluble
530 Prussian blue was less effective (Dresow et al., 1993).
531
532 9.1.1.2 Enhancement of decorporation (reduced retention)
533 Chronic feeding of rats (Dresow et al., 1993; Stather, 1972) or piglets (Dresow et al., 1993;
534 Giese et al., 1970) with caesium-137 contaminated food and concomitantly administration of
535 Prussian blue resulted in reduced whole body retention. Most of the daily caesium-137 dose
536 was excreted in the faeces.
537
538 After ingestion of radiocaesium, administration of insoluble Prussian blue (Bozorgzadh &
539 Catsch, 1972; Dresow et al., 1990; Nigrovi, 1963; Nigrovi, 1965; Nigrovi et al., 1966;
540 Stather, 1972;) and colloidal soluble Prussian blue (Bozorgzadeh, 1971; Bozorgzadh &
541 Catsch, 1972; Dresow et al., 1990; Giese et al., 1970; Mller et al., 1974) decreased the
542 whole-body-retention of the caesium isotopes. Also in a mixture with other substances
543 Prussian blue increased the excretion of the caesium-137 (Kostial et al., 1983). In rats the
544 effect on the whole-body retention was age-dependent. In younger animals the whole body
545 retention was lower than in older animals. Probably because of the higher basal metabolic
546 rate more caesium was excreted into the gut in young animals (Bozorgzadeh, 1971; Stather,
547 1972).
548
549 Prussian blue increased the cumulative excretion of incorporated radiocaesium in faeces and
550 urine (Brenot & Rinaldi, 1967; Nigrovi, 1965; Nigrovi et al., 1966). Whereas in untreated
551 animals most caesium is excreted in the urine, in animals treated with Prussian blue faecal
552 excretion predominates (Nigrovi et al., 1966; Brenot & Rinaldi, 1967; Mller, 1969; Giese
553 et al., 1970; Giese & Hantzsch, 1970; Richmond, 1968). The biological half-life was
554 reduced (Madshus et al., 1966; Nigrovi et al., 1966; Havliek et al., 1967; Havliek, 1968;
555 Mller et al., 1974; Richmond, 1968; Strmme, 1968). In rats the half-life was reduced by
556 50% (11 days compared to 6 days) (Nigrovi et al., 1966; Mller et al., 1974), and in dogs
557 from 11 to 6.5 days (Madshus et al., 1966).
558
559 Colloidal soluble Prussian blue was more efficient in increasing the excretion of
560 radiocaesium than the insoluble form (Mller, 1969). In long-term use however, colloidal
561 soluble Prussian blue decreased the excretion compared with control animals. Insoluble
562 Prussian blue did not show this effect (Bozorgzadh & Catsch, 1972). After thorough
563 dialysis with water to remove any possible low molecular impurities this effect of the
564 colloidal Prussian blue disappeared (Mller et al., 1974). The efficacy of the dialyzed
565 colloidal soluble Prussian blue, however, was only marginally better than that of insoluble
566 Prussian blue (biological half-lives: control 10.51 days, insoluble Prussian blue 5.6 days,
567 colloidal Prussian blue 4.88 days) (Mller et al., 1974).
13
568
569 The efficacy of therapy with Prussian blue is time-dependent. The best effect resulted in
570 administration of Prussian blue 2 minutes before application of caesium (Dresow et al.,
571 1990). Start of treatment immediately after intoxication was also successful (Bozorgzadh,
572 1971; Bozorgzadh & Catsch, 1972), but it was still effective after a delayed start of 3.5
573 days (Stather, 1972).
574
575 The reduced whole-body retention of caesium after treatment with Prussian blue can also be
576 seen in individual organs. This reduced caesium content of the different organs has been
577 reported in muscle (Bozorgzadh, 1971; Bozorgzadh & Catsch, 1972; Brenot & Rinaldi,
578 1967; Kostial et al., 1983; Mller et al., 1974; Stather, 1972; Wolsieffer et al., 1969), bone
579 (Bozorgzadh & Catsch, 1972; Mller et al., 1974; Wolsieffer et al. 1969), carcass (Kostial
580 et al., 1983; Wolsieffer et al. 1969), liver (Bozorgzadh, 1971; Mller et al., 1974; Stather,
581 1972) and kidney (Bozorgzadh, 1971; Bozorgzadh & Catsch, 1972; Brenot & Rinaldi,
582 1967; Kostial et al., 1983; Mller et al., 1974; Stather, 1972). Due to a different turnover
583 rate of the organs the rate of diminution of caesium in the different organs varied. In the
584 gastrointestinal-tract the caesium content was increased due to binding on the non-resorbable
585 Prussian blue (Brenot & Rinaldi, 1967).
586
587 After 15 days of dietary acclimatization to insoluble Prussian blue as 1% of their food, rats
588 were given intraperitoneal casesium-137. The animals were killed 30 days later. There was
589 significant reduction in the retention of caesium-137 in the carcass, femur and muscle
590 (Wolsieffer et al., 1969).
591
592 Oral insoluble Prussian blue was given to rats in drinking water (400 mg/kg/day) for 11 days
593 which was started immediately after an intravenous injection with caesium-137. On
594 evaluation at 11 days Prussian blue had increased the faecal excretion of caesium-137 5-fold
595 and this consequently also reduced urine excretion. There was also reduced retention of Cs-
596 137 in all the tissues tested (blood, liver, kidneys, spleen and skeleton) (Le Gall et al., 2006).
597
598 Oral administration of insoluble Prussian blue shortened the retention of caesium-137 in
599 mated, pregnant and lactating rats and the deposition of caesium-137 in the embryos and
600 nursed young animals was reduced (Havliek, 1967; Havliek, 1968).
601
602 The effect of Prussian blue provided in drinking water to rats of various ages, on the
603 excretion of intraperitoneally administered caesium-137 was investigated. In 19-week old
604 rats the body burden of caesium-137 was reduced to 34% of the controls 1 week after
605 injection whilst in 9-week and 4-week old rats, the corresponding values were 28% and 9%
606 respectively. Tissue analysis suggested that the rate limiting factor of excretion of caesium-
607 137 during Prussian blue therapy was the turnover rate of caesium-137 in muscle tissue. The
608 turnover rate of caesium-137 in muscle tissues of young animals is faster than that of older
609 animals and this is reflected in an increased efficacy of Prussian blue in removing caesium-
610 137 from the younger animals (Stather, 1972).
611
612 9.1.1.3 Impact on outcomes
613 Richmond & Bunde, (1966) investigated the effect of three different concentrations of
614 Prussian blue on caesium-137 contaminated rats. Each rat (approximately 92 days old with
615 and average bodyweight of 372g) received approximately 0.84 microcurie of caesium-137,
616 the rats were then measured 30 minutes later for total body activity and then returned to their
617 respective cages. Insoluble Prussian blue was incorporated into their drinking water which
14
618 they had free access to over the following 60 days. The concentrations of Prussian blue in
619 the water were 0, 0.025, 0.25 and 2.5 g/L, and the estimated daily dose of Prussian blue was
620 0, 0.9, 8.5 and 84 mg/rat, respectively. There was significant reduction in the whole body
621 retention of caesium-137 with continuous ingestion of Prussian blue at 0.25 and 2.5 g/L, but
622 no effect was observed at 0.025 g/L. Retention of caesium was described in 3 exponential
623 terms and the third component had a half-life of 8.77 days in high-dose Prussian blue rats
624 compared to 14 days in control rats. The authors concluded that the rate of caesium-137
625 secretion would depend partially on the turnover rate in body tissues, particularly muscle,
626 which accounts for a large proportion of the total body caesium-137 activity.
627
628 The effect of Prussian blue was studied in sheep fed wheat and grass contaminated with
629 caesium after the Chernobyl accident. The lactating sheep (average 35 kg) were given 0.5
630 kg of wheat (average radiocaesium content 1684 17 Bq/kg) and 200 g (9840 442 Bq/kg)
631 daily. The average milk yield was 110 g per day. When the radiocaesium content of the
632 milk had reached a state of equilibrium half the animals were given colloidal Prussian blue,
633 5 g in 5 L of drinking water for 23 days. The colloidal Prussian blue settled in the container
634 and the drinking water had to be stirred repeatedly during the day and it took about 2 days
635 before the sheep became used to the water. Treatment with Prussian blue reduced the
636 radiocaesium content of the milk by approximately 85% and the effect was seen within a few
637 days of the start of treatment (Ioannides et al., 1991).
638
639 The role of Prussian blue in removing caesium-137 internal contamination from rats was
640 studied to evaluate the possible side effects caused by chronic consumption on various
641 biomarkers for exposure. Rats of two age groups (growing rats (2-months old) and adult rats
642 (4month old)), were observed over a 60 day period having had either caesium-137 alone,
643 Prussian blue alone, or a combination of both, administered at different time intervals (e.g.
644 both given simultaneously or with a time lapse between). The authors reported that in both
645 growing and adult rats Prussian blue administration, particularly when given before or
646 immediately after Caesium-137 intake, could eliminate the effects of caesium-137
647 irradiation on red blood cell count and haemoglobin content, and on serum levels of: total
648 proteins (in adult rats only), globulins (in adult rats only), creatinine, urea, urea nitrogen,
649 ALT activity, T3, and T4. When given one or seven days post caesium-137 irradiation,
650 Prussian blue eliminated the effects of caesium-137 treatment on serum cholesterol, serum
651 calcium and serum bilirubin, in both growing and adult rats (Fekry et al., 2003).
652
653 The efficacy of insoluble and colloidal soluble Prussian blue in removing a single dose of
654 internally deposited caesium-134 was compared in rats (6 rats in each experimental group).
655 Prussian blue was administered twice daily and treatment started immediately after injection
656 of caesium-134. For the first few days the colloidal form initially showed greater efficacy in
657 removing the caesium but with continuous administration it brought about a complete
658 blockage of caesium-134 excretion from the liver, spleen and skeleton. This was attributed
659 to in vivo disintegration of the colloidal compound yielding free [Fe(CN)6]4- which when
660 absorbed from the gut reacts with endogenous metal ions. The authors highlight the practical
661 clinical consequences of this finding in that the insoluble compound should be the antidote
662 of choice for caesium-134 toxicity; the slight transient superiority of the colloidal form is
663 over-shadowed by its untoward long-term effect (Bozorgzadh & Catsch, 1972).
664
665 9.1.2 Rubidium
666 There is limited information on the decorporation effect of Prussian blue in rubidium
667 exposure. Rats were fed insoluble Prussian blue in their food (as 5%) from 2 days before an
15
668 intraperitoneal injection of rubidium-86. Prussian blue reduced the half-life of rubidium-86
669 from 10.3 days to 1.7 days, reducing the whole body retention to 9% that of controls after 7
670 days (Stather, 1972).
671
672 9.1.3 Thallium
673
674 9.1.3.1 Prevention of absorption/uptake from gut
675 Concomitant oral administration of thallium and of Prussian blue in rats resulted in a lower
676 uptake of the metal and lower concentrations found in organs (Dvok, 1969; Heydlauf,
677 1969; Rauws, 1974). Soluble Prussian blue was more effective than the insoluble Prussian
678 blue (Dvok, 1969).
679
680 In a study by Heydlauf (1969) aqueous solutions of thallium-204 sulphate were administered
681 to rats by gastric tube. Aqueous suspensions of ferric cyanoferrate (II) (insoluble Prussian
682 blue) in doses of 0.5-50 g were then administered by gastric tube 1 to 60 minutes later. The
683 maximal protective effect, i.e. approximately ten times lower absorption of thallium-204,
684 was observed when Prussian blue was given immediately, although an effect was still seen
685 when Prussian blue was administered at 60 minutes. As expected, there was a marked
686 dependence of antidotal efficacy on the dose of Prussian blue administered.
687
688 9.1.3.2 Enhancement of decorporation (reduced retention)
689 It was also shown that insoluble Prussian blue was able to remove thallium across the
690 gastrointestinal wall. Carrier-free thallium-204 was injected intravenously and the animals
691 fed with Prussian blue pellets at will (Heydlauf, 1969). The thallium-204 content of
692 Prussian blue treated animals was drastically reduced even when treatment was initiated on
693 the fourth day. This was due to markedly enhanced faecal excretion whereas urinary
694 elimination did not reach the control level.
695
696 Insoluble Prussian blue (Heydlauf, 1969) as well as colloidal soluble Prussian blue (Dvok,
697 1969; Gnther, 1971) reduced the retention of thallium in the body. The excretion in the
698 faeces was increased and decreased in the urine when compared to the control animals
699 (Heydlauf, 1969; Lehmann & Favari, 1985; Leloux et al. 1990; Manninen et al., 1976;
700 Rauws, 1974; van der Stock & de Schepper, 1978). The cumulative excretion in faeces and
701 urine was increased (Heydlauf, 1969; Lehmann & Favari, 1985; Rauws, 1974). The bio-
702 logical half-life of thallium in the body was reduced. In dogs the biological half-life was
703 decreased from 6.5 days (measured in control animals) to 2.5 days (animals treated with
704 Prussian blue) (van der Stock & de Schepper, 1978), in rats it was decreased from 4 days to
705 2 days (Rauws, 1974).
706
707 A study in rats demonstrated that soluble Prussian blue increased excretion of thallium and
708 reduced the LD50 but only if started within 24 hours of exposure. Thereafter thallium-
709 induced pathological changes were irreversible (Gnther, 1971).
710
711 The reduced retention and the increased excretion of thallium by Prussian blue results in a
712 decrease of the thallium content in liver (Dvok, 1969; Gnther, 1971; Heydlauf, 1969;
713 Kravzov et al., 1993; Manninen et al., 1976; Ros & Monroy-Noyola, 1992; Sabbioni et al.,
714 1982), kidney (Dvok, 1969; Gnther, 1971; Heydlauf, 1969; Kravzov et al., 1993;
715 Manninen et al., 1976; Rauws, 1974; Ros & Monroy-Noyola, 1992; Sabbioni et al., 1982),
716 skeleton (Heydlauf, 1969) blood (Ros et al., 1991), heart (Kravzov et al., 1993; Ros &
717 Monroy-Noyola, 1992) and muscles (Dvok, 1969; Gnther, 1971; Heydlauf, 1969;
16
718 Manninen et al, 1976; Rauws, 1974).

719
720 9.1.3.3 Impact on outcomes
721 Kamerbeek et al. (Kamerbeek, 1971; Kamerbeek et al., 1971) showed the influence of
722 Prussian blue on the concentration of thallium in the brain. Thirty-five rats, divided into
723 seven groups of five animals, were given 0.075 mM/kg thallous nitrate in 5% glucose
724 solution by intraperitoneal injection. After 24 hours, one group was sacrificed. Three of the
725 remaining groups were subsequently treated with 50 mg Prussian blue suspended in saline,
726 twice daily by gavage. The other groups served as controls. At 48, 72 and 120 hours after
727 administration of thallium, one control and one treated group were killed. The thallium
728 concentration was determined in the brain and in a muscle specimen (quadriceps). After
729 four days of Prussian blue therapy the concentration of thallium in the brain of the treated
730 groups was less than half that of the control group. The muscle thallium concentration in the
731 treated group was almost one-fourth of that of the control group. A dose-dependent
732 relationship was observed. Also in other experiments reduced thallium levels in the brain
733 were measured (Kravzov et al., 1993; Leloux et al., 1990; Manninen et al., 1976; Rauws.
734 1974; Ros et al., 1991; Ros & Monroy-Noyola, 1992; Sabbioni et al., 1982).
735
736 Trying to establish an optimal dosage scheme for use of Prussian blue in human
737 thallotoxicosis, Kamerbeek (1971) gave five groups of five rats 0.1 mm/kg thallous nitrate
738 intraperitoneally. After 24 hours four groups were treated by gavage once daily with 10, 50,
739 250 and 1000 mg/kg Prussian blue, suspended in 15% mannitol. After four days of
740 treatment, the animals were sacrificed and the thallium concentrations were determined in
741 the brain and in a muscle specimen. A daily dose of 250 mg/kg Prussian blue appeared to be
742 as effective as 1000 mg/kg/day with respect to thallium-concentration in muscle specimen
743 but with respect to thallium in the brain the highest dosage was more efficacious.
744
745 Kamerbeek (1971) further investigated the protection afforded by Prussian blue against
746 thallium toxicity. Two groups of rats were given 0.25 mg/kg thallous nitrate intraperi-
747 toneally. Four hours later one group received Prussian blue 100 mg/kg in a 15% mannitol
748 solution by gavage. The other group received mannitol only. This regimen was repeated for
749 10 days. In the control group, 10 of 20 animals died, while in the treated group only two
750 deaths occurred.
751
752 It was further shown that enhanced thallium-204 excretion as a result of Prussian blue
753 therapy was accompanied by reduced thallium toxicity (Kravzov et al., 1993; Ros et al.,
754 1991; Ros & Monroy-Noyola 1992). Treatment with potassium ferric hexacyanoferrate (II)
755 (colloidal soluble Prussian blue) increased the LD50 by a factor 2.3 (Gnther, 1971). After
756 application of 30 mg thallium/kg the survival in the control group was 0% and in the
757 Prussian blue group 50% (Heydlauf, 1969).
758
759 After intraperitoneal injection of thallium (32 mg/kg) on day 1, a group of 16 rats was given
760 soluble Prussian blue (50 mg/kg orally twice daily), D-penicillamine (intraperitoneal
761 injection 25 mg/kg) or a combination of the two from days 2 to 5. The mortality in the
762 different treatment groups by day 6 was: control group 87.5%, Prussian blue group 56.25%,
763 D-penicillamine group 100% and Prussian blue + D-penicillamine group 25%. Only the
764 combination of antidotes produced a significant difference in mortality compared to controls.
765 Prussian blue alone protected against thallium-induced neurotoxicity (as measured by the
766 number of altered Purkinje cells) but the effect was greater with combined Prussian blue +
767 D-penicillamine. D-penicillamine alone did not protect against thallium-induced changes in
17
768 Purkinje cells (Barroso-Moguel et al, 1994).

769
770 9.2 Pharmacokinetics
771
772 9.2.1 Oral
773 There is limited information on the pharmacokinetics of Prussian blue as these compounds
774 are very poorly absorbed from the gastrointestinal tract. Most studies have been performed
775 with iron-59 or carbon-14 labelled Prussian blue examining intestinal absorption and
776 bioavailability of iron and cyanide (see section 9.4 for studies on assessment of cyanide
777 toxicity).
778
779 The release of iron from potassium ferric (III) hexacyanoferrate (II) and ferric (III)
780 hexacyanoferrate (II) was examined in piglets. The compounds were labelled with iron-59
781 in the ferric or ferrous position. When labelled in the ferric position only 1.47% of the iron
782 was absorbed from potassium ferric (III) hexacyanoferrate (II) and 1.34% from ferric (III)
783 hexacyanoferrate (II), as determined by the whole-body retention 14 days after oral dosing.
784 Only 0.2% and 0.15%, respectively, of the iron was absorbed from the ferrous position.
785 Most of the dose was excreted in the faeces; 0.1 to1% of the iron-59 was in the urine but it
786 could not be determine how much of may have been due to faecal contamination (Nielsen et
787 al., 1988a). This study suggests that iron is not significantly absorbed from Prussian blue.
788
789 Administration of labelled (59Fe, 14C) Prussian blue to rats resulted whole-body retention of
790 0.03% of the dose (only in the gastrointestinal tract) and in traces of radioactivity in the
791 urine (0.15%). The amount in blood and skeleton was below the detection limit. After
792 administration of iron-59 labelled potassium ferric (III) hexacyanoferrate (II)
793 (K59Fe[Fe(CN)6]) to rats traces of radioactivity were found in the skeleton (0.11% of the
794 administered dose) and in blood (0.046%). Again, with radio-labelled iron in the ferric and
795 ferrous positions, the differences in distribution showed that Prussian blue is not absorbed,
796 but the different ions K+, Fe3+ and [Fe(CN)6]4- are metabolized instead. No evidence was
797 obtained for decomposition of [Fe(CN)6]4- (Dvok et al., 1971). Histopathological
798 examination of organs showed no deposits of Prussian blue after oral administration of
799 insoluble and colloidal soluble Prussian blue (Giese & Hantzsch, 1970).
800
801 9.2.2 Parenteral
802 After intraperitoneal administration of radio-labelled colloidal soluble Prussian blue the
803 substance is eliminated by the reticuloendothelial system. On the first day 40.5% of the
804 radioactivity was excreted in the urine, the content in the faeces was very small. On the
805 second day 42% was found in the faeces with only traces in the urine. After 4 days the body
806 retention was 4.5%, mostly in the liver (Mller, 1969).
807
808 Intravenous administration of KFe[59Fe(CN)6] and K59Fe[Fe(CN)6] resulted in entirely
809 different metabolic behaviour in rats between the two forms. With potassium ferric (III)
810 hexacyanoferrate (II) labelled in the ferrous position (KFe[59Fe(CN)6]) more than 50% of the
811 radioactivity was excreted in the urine, by contrast when labelled in the ferric position
812 (K59Fe[Fe(CN)6]) only 0.06%. The faecal excretion was low for both. The distribution of
813 the radioactivity into the organs after administration of KFe[59Fe(CN)6] differed from that of
814 K59Fe[Fe(CN)6]. Whereas the radioactivity of KFe[59Fe(CN)6] persisted in the liver for 8
815 days, the activity of K59Fe[Fe(CN)6] varied from the liver to the blood (Dvok et al., 1971).
816
817 9.3 Toxicology
18
818
819 9.3.1 Acute toxicity
820 Ferric (III) hexacyanoferrate (II)
821 Oral:
822 According to a Soviet study, 8g/kg body weight was not lethal to laboratory animals
823 (presumed to be rats or mice) and produced no clinical signs of toxicity (BIBRA, 1997)
824
825 Intraperitoneal administration:
826 LD50 rat: 1.13 mg/g body weight (Brenot & Rinaldi, 1967).
827 LD50 rat: 2.1g/kg body weight (BIBRA, 1997).
828 LD50 mouse: 2 g/kg body weight (BIBRA, 1997).
829
830 Rats or mice given lethal doses suffered inertia, breathlessness and sluggishness with excess
831 blood in the liver, spleen and kidney (BIBRA, 1997).
832
833
834 Potassium ferric (III) hexacyanoferrate (II)
835 In studies by Dvok et al. (1971) the lethality of intravenous injection of 1 mg of colloidal
836 soluble Prussian blue in rats varied from 0% to 100%, despite the same manufacturing
837 processes. Some animals became unwell within 15 minutes and developed respiratory
838 distress. A blue colouration was noted in the lungs at post-mortem examination. This
839 variation in toxicity was thought to be due to differences in the degree of dispersion of the
840 Prussian blue in the solution of each batch.
841
842
843 Pigment blue 27
844 Oral LD50 rat: >5g/kg body weight (BIBRA, 1997).
845
846
847
848 9.3.2 Chronic toxicity
849 In rats colloidal soluble Prussian blue given as 2% of drinking water for 12 weeks resulted in
850 no significant body weight changes or histopathological changes in the organs, including the
851 gut (Dvok et al., 1971). Similarly, sheep (average weight 35 kg) given colloidal soluble
852 Prussian blue, 5 g in 5 L of drinking water daily for 23 days had no change in body weight
853 (Ioannides et al., 1991).
854
855 There were no significant differences in average fluid intake in rats given insoluble Prussian
856 blue in drinking water (0.025, 0.25 or 2.5 g/L) for 60 days. The estimated daily dose of
857 Prussian blue was 0.9, 8.5 and 84 mg/rat, respectively (equating to 2.4, 23, 226 mg/kg)
858 (Richmond & Bunde, 1966).
859
860 Oral insoluble Prussian blue caused no adverse effects and no impairment of growth in
861 young rats when given as 1% of the diet for 120 days (Nigrovi et al., 1966) or as 1% of
862 their food for 60 days in rats (Wolsieffer et al., 1969). Also in rats, food consumption and
863 body weight were unchanged during 9 days of treatment with a mixture of sodium alginate
864 (daily consumption 2 g), insoluble Prussian blue (250 mg) and sodium perchlorate (100 mg)
865 (Kostial et al., 1980) or during 4 weeks treatment with a mixture of calcium alginate
866 (average 4.8 g/day), insoluble Prussian blue (average 0.8 g/day) and potassium iodide
867 (0.0048 g/day) (Kostial et al., 1981).
19
868
869 There were no adverse effects in dogs (7 to 8 kg) given oral insoluble Prussian blue (3 or 6
870 doses of 0.5 g daily) for 11 days. The doses equate to approximately 200 and 400 mg/kg,
871 respectively (Madshus et al., 1966). At autopsy no pathological changes were observed
872 (Nigrovi et al., 1966).
873
874 9.3.3 Reproductive toxicology and teratogenicity
875 There is no information available on the reproductive toxicity of Prussian blue.
876
877 In pregnant rats intoxicated with oral thallium soluble Prussian blue started 8 hours later
878 increased the survival rate, reduced the thallium content of the placenta by 5-fold and in the
879 foetuses reduced the thallium content of the brain and liver (Sabbioni et al., 1982).
880
881 9.3.4 Genotoxicity
882 No information available.
883
884 9.4 Assessment of possible cyanide toxicity
885 Prussian blue contains cyanide ions bound to iron. At extremely low pH values in the
886 presence of oxidizing agents Prussian blue decomposes and, under these circumstances,
887 cyanide can be released. Since oral administration of Prussian blue is indicated in the
888 treatment of thallium poisoning and caesium incorporation, various studies have examined
889 the possibility of cyanide release from these hexacyanoferrate compounds.
890
891 When gastric juice (pH 2) and soluble Prussian blue were incubated for 4 hours no cyanide
892 was detected. Similarly no cyanide was detected when the study was conducted with 0.1 N
893 hydrochloric acid at room temperature. Cyanide was only detected when this last
894 experiment was repeated at 100 C (Kamerbeek, 1971). Other in vitro studies have also
895 shown that the release of cyanide is negligible (Dvok, 1970).
896
897 Verzijl et al. (1993) studied in vitro cyanide release of four Prussian blue salts, potassium
898 ferric (III) hexacyanoferrate (II), ferric (III) hexacyanoferrate (II) and ammonium ferric (III)
899 hexacyanoferrate (II), both unpurified and purified compounds (that is, with and without
900 33% ammonium chloride as a manufacturing impurity). These salts were added to water,
901 artificial gastric (pH 1.2) or intestinal (pH 6.8) juices and the content flasks were allowed to
902 stand for 5 hours, protected from light, at 370C. Cyanide was detected in all tests and the
903 quantity released ranged from 22 to 535 g/g of Prussian blue in water, 64 to 418 g/g in
904 artificial gastric juice and 15 to 58 g/g in artificial intestinal juice. For all salts tested the
905 release of cyanide was greatest in artificial gastric juice than the other test media. The
906 unpurified ammonium ferric (III) hexacyanoferrate (II) released the most cyanide and ferric
907 (III) hexacyanoferrate (II) (insoluble Prussian blue) the least in all test media.
908
909 In an in vitro study the release of cyanide from insoluble Prussian blue was measured over a
910 pH range of 1.0 to 12 following incubation for 1 to 48 hours in a shaking water bath at 370C
911 (Yang et al., 2007). Five batches of active pharmaceutical ingredients were tested and three
912 batches of drug product. The release of cyanide was both pH-dependent and incubation-time
913 dependent. The greatest release occurred at pH 1.0 with a gradual decline as the pH
914 increased to 7.0. At this pH the lowest quantity of cyanide was released and as the pH
915 increased again the cyanide concentration also increased. Increasing the incubation time at
916 different pH also increased the amount of cyanide released. The highest cyanide
917 concentration occurred when Prussian blue was incubated at pH 1.0 for 48 hours. The
20
918 authors concluded that, based on a dose of 17.5 g of Prussian blue per day, a total of 1.5-1.6
919 mg of cyanide would be released, which was well below the minimum toxic dose of cyanide
920 of 14.4 mg.
921
922 The release of cyanide from potassium ferric (III) hexacyanoferrate (II) and ferric (III)
923 hexacyanoferrate (II) was examined in piglets. The compounds were labelled with carbon-
924 14 in the cyanide group. No carbon-14 dioxide was detected in expired air after ferric (III)
925 hexacyanoferrate (II), indicating that the quantity of cyanide released is very small or nil
926 (Nielsen et al., 1988a).
927
928
929 10. Volunteer Studies

930
931 10.1 Pharmacokinetics
932 There is very little published pharmacokinetic data on Prussian blue in humans.
933
934 10.1.1 Release of iron and cyanide from Prussian blue
935 Three volunteers (all male, 36 years, 81 kg; 38 years, 81 kg; 45 years, 70 kg) were given
936 radio-labelled soluble Prussian blue (500 mg) to determine the release of iron and cyanide in
937 humans in vivo. The compound was labelled with iron-59 in the ferric or ferrous position
938 and carbon-14 in the cyanide group. Only 0.22% of iron (II) and <0.04% of iron (III) was
939 absorbed. Only 2 mg of non-complex bound carbon-14 labelled cyanide was absorbed. This
940 is a factor of 20 to 100 below the lethal dose of 0.5 to 3.5 mg cyanide/kg in humans (Nielsen
941 et al., 1990a).
942
943 10.2 Caesium
944
945 10.2.1 Studies on absorption
946 In a series of volunteer studies on the effect of Prussian blue on the pharmacokinetics of
947 caesium the studies involved self-dosing by the study authors. These authors (to include 8
948 observations, 5 volunteers undertook the study once and one author repeated the experiment
949 twice) showed that 3 g daily of Prussian blue given before caesium-137 did not reduce
950 caesium absorption. The increase in caesium-137 excretion was small following 0.5 g of
951 Prussian blue three times daily (Madshus & Strmme, 1968).
952
953 In 6 volunteers a preliminary study showed that insoluble Prussian blue (4 x 0.5 g or 10 x
954 0.2 g daily for 2 to 3 weeks) did not fully block caesium uptake from contaminated food
955 (Volf et al., 1987).
956
957 Two male volunteers (age 36 and 38 years, both 81 kg) ingested three single test meals
958 consisting of 170 g of milk labelled with a tracer dose of caesium-134 along with bread,
959 margarine and cheese 10 minutes after ingestion of 1 g of Prussian blue in gelatine capsules.
960 Both forms of Prussian blue were equally effective in reducing radiocaesium absorption.
961 The absorption of radiocaesium from the meal judged by urinary excretion of caesium-134
962 and whole body retention 14 days after administration was reduced from 100.9% (control
963 without Prussian blue) to 5.6% by soluble Prussian blue and to 6.4% by insoluble Prussian
964 blue (Dresow et al., 1993). In a similar study in two male adult volunteers, the ingestion of
965 Prussian blue ten minutes before eating a test meal containing caesium-134 labelled milk
966 (along with bread, margarine and cheese) reduced the caesium absorption more than the
21
967 simultaneous administration of Prussian blue along with the labelled test meal.
968 Administration of Prussian blue prior to the meal reduced absorption of the radiocaesium to
969 3-10% of the ingested dose whereas simultaneous ingestion of Prussian blue and the test
970 meal only reduced absorption to 38-63%. The 100% control was the absorption rate of the
971 radiocaesium test meal alone without Prussian blue (Nielsen et al., 1991).
972
973 10.2.2 Studies on decorporation/excretion
974 In a series of volunteer studies on the effect of Prussian blue on the pharmacokinetics of
975 caesium the studies involved self-dosing by the study authors. Studying the decorporation
976 of caesium involved ingestion of Prussian blue (3 g daily as 2 or 3 doses for several weeks)
977 in 2 adult males given 180 days after ingestion of caesium-137 and it was found to reduce
978 the biological half-life of caesium from the pre-treatment values of 110 and 115 days to 40
979 days. The only adverse effect was mild constipation (Madshus et al., 1966).
980
981 In five cases when Prussian blue (1g three times daily) was given several months after
982 caesium ingestion the biological half-life of caesium was reduced on average from 94 to 31
983 days, that is, to one third of its original half-life (Madshus & Strmme, 1968; Strmme,
984 1968).
985
986 A 37-year-old male was given oral caesium-137 for 24 days followed by 2 g of insoluble
987 Prussian blue (as 10 x 200 mg daily over a 9 hours period) from day 12 to day 17 then after a
988 rest period of 2 days was given Prussian blue for another 5 days. The biological half-life of
989 the caesium was reduced from 140 days to approximately 50 days. There was no
990 constipation and no change in whole-body potassium values (Richmond, 1968).
991
992 Fifteen Chinese exchange students in Bulgaria were exposed to caesium-134 and 137
993 released following the accident at the Chernobyl Nuclear Power Station in April 1986, and
994 following their return to China in June they were assessed for contamination. In three
995 volunteers the biological half-life of caesium ranged from 42 to 71 days. Insoluble Prussian
996 blue (1 g three times daily for 6 days repeated for 3 courses with a 6 day rest period in
997 between) was given from day 114 to 145 after exposure. This reduced the half-life of
998 caesium and enhanced elimination (Tang et al., 1988).
999
1000 10.3 Rubidium exposure
1001 There are no volunteer studies on the effect of Prussian blue in rubidium exposure.
1002
1003 10.4 Thallium poisoning
1004 There are no volunteer studies on the effect of Prussian blue in thallium exposure.
1005
1006 Bhardwaj et al. (2006) studied the effect of insoluble Prussian blue on whole body
1007 radioactivity in two patients following thallium-201 myocardial scintigraphy. Each patient
1008 had two sessions of scintigraphy, one with and one without Prussian blue (100 mg 3 times
1009 daily after meals for 3 days), so each patient acted as their own control. In the first patient
1010 whole body radioactivity was reduced by 18 and 30% after 24 and 48 hours, respectively, of
1011 oral Prussian blue therapy. The second patient developed constipation and did not pass any
1012 stools after oral Prussian blue for 48 hours. The whole body radiation counts were similar to
1013 those when Prussian blue was not given but there was a concentration of radioactivity in the
1014 colon suggesting that the radioactivity was unavailable for resorption.
1015
1016
22
1017 11. Clinical Studies Clinical Trials

1018
1019 There are no controlled clinical trials on the use of Prussian blue in human thallium poisoning or
1020 radiocaesium decorporation.
1021
1022
1023 12. Clinical Studies - Case Reports

1024
1025 12.1 Decorporation of radiocaesium
1026
1027 12.1.1 Goinia incident, Brazil, 1987
1028 At the end of 1985 a private radiotherapy institute moved premises and left a caesium-137
1029 teletherapy unit behind. The building was partly demolished and in 1987 two men removed
1030 the source assembly head from the machine thinking it may have scrap value but without
1031 being aware of what it was. They took this home and tried to dismantle it during which they
1032 ruptured the source capsule. This contained caesium chloride which is highly soluble and
1033 easily dispersed. After the rupture the source capsule was sold for scrap to a junkyard
1034 dealer. He observed that the material glowed blue in the dark and over the next 5 days this
1035 was a source of interest to family and friends. During this time several individuals started to
1036 become unwell with gastrointestinal signs and eventually the source capsule was suspected
1037 and it was taken to the public health department. This triggered a major response to the
1038 incident. In total 112,000 people were assessed and 249 were found to contaminated either
1039 internally or externally with caesium-137. Some had very high exposure due to eating with
1040 contaminated hands or rubbing the glowing material over their body. Twenty patients
1041 developed bone marrow suppression. Eight developed acute radiation syndrome (Brando-
1042 Mello et al., 1991) and four of these victims died within 4 weeks of their admission to
1043 hospital (IAEA, 1988). Prussian blue (Radiogardase-Cs) treatment was given to 46
1044 patients (aged 4 to 46 years) for up to 150 days. The adults were initially given 3 g daily and
1045 the 13 children were given 1 to 1.5 g daily. These doses were later increased to 10 g and 3 g
1046 daily, respectively, when it was established that larger doses resulted in higher radioactivity
1047 of faecal samples. In four cases 20 g of Prussian blue was given over 24 hours. Of 46
1048 patients, 10 developed mild to moderate constipation and this was managed with a high fibre
1049 diet or laxatives (Farina & Brando-Mello, 1991). Prussian blue treatment significantly
1050 increased the rate of faecal caesium excretion and reduced whole body retention of caesium
1051 (IAEA, 1988). The physiological faeces to urine excretion ratio of caesium was 1:4 and this
1052 was changed to 4:1 with Prussian blue treatment (Farina & Brando-Mello, 1991). In 15
1053 adult patients who received Prussian blue the body burden of caesium-137 was reduced by
1054 51% to 84% with an average of 71% within the first 2 months after exposure. This dose
1055 reduction was independent of the Prussian blue dose in the range of 3 to 10 g/day (Melo et
1056 al., 1994).
1057
1058 In vivo data from patients internally contaminated with caesium-137 in the Goinia accident
1059 was analysed to compare the half-life of caesium-137 with and without Prussian blue
1060 treatment. Additionally the possible influences of various body parameters (age, height,
1061 weight and radioactivity) on the half-lives were evaluated. Subjects were monitored using a
1062 whole-body counter and the findings are from data collected for the period of one year post
1063 the accident. Patients under treatment had previously followed different Prussian blue dosing
1064 patterns but during the monitoring period received 3 g/day, 6 g/day or 10 g/day. Caesium-
1065 137 elimination from the body followed first order kinetics with or without Prussian blue
23
1066 therapy. Without Prussian blue treatment the half lives of caesium-137 in the 10 adult
1067 females studied varied widely (range 39 to 104 days; mean: 65.5 days) with less variation
1068 seen in the 8 adult males (66 to 106 days; mean: 83 days). Overall Prussian blue reduced the
1069 half-life of caesium-137 by about 32%. The actual calculations showed that for those
1070 subjects receiving 3 g/day of Prussian blue the mean reduction was 28%, it was 31% in those
1071 receiving 6 g/day and was 32% in subjects receiving 10 g/day. The strongest parameter
1072 influencing the half-life in both males and females was body weight. Height and age were
1073 correlated to the half-lives through their correlation to the weight parameter but were not
1074 additional variables. Investigating the estimated caesium-137 body burden at the initial time
1075 of elimination found an inverse relationship between initial activity and half-life: the larger
1076 the initial body burden, the faster the nucleotide removal from the body. The influence of
1077 this parameter was much weaker than that of body weight (Lipsztein et al., 1991).
1078
1079 12.1.2 Chernobyl incident, 1986
1080 Measurements were made on 15 Chinese subjects internally contaminated with
1081 radionucleotides released from the Chernobyl accident on 26th April 1986. The students had
1082 been visiting Sofia, Bulgaria from 19th April until 23 May 1986 and monitoring was done on
1083 their return to Beijing. Internal contamination with radioactive caesium (caesium-134 and
1084 caesium-137) was measured in all 15 students. The measured activity in the body for the 15
1085 volunteers ranged from 68-840 Bq for cesium-137 and 110-630 Bq for caesium-134. The
1086 estimated intakes were calculated and ranges were 95-1200 Bq (Caesium-137) and 170-930
1087 Bq (Caesium-134). The biological half-life was calculated for three volunteers along with
1088 the effect of Prussian blue on their rate of elimination of radiocaesium. Prussian blue was
1089 given at doses of 1g three times a day for a 6 day course, 3 courses in total were give with a
1090 6 day time interval between each course. The biological half-life of the radiocaesium ranged
1091 from 43-71 days. Prussian blue was given to the three volunteers in the period of 114-141
1092 days after contamination and the body retention of radiocaesium declined more rapidly
1093 following Prussian blue administration than in those of controls (Tang et al., 1988).
1094
1095 12.1.3 Other case reports
1096 Five persons, two adults (aged 34 and 38 years, weight 56 and 55 kg) and three children
1097 (aged 4 to 11 years; weight 13.5 to 34 kg) accidentally received caesium-137 chloride for
1098 approximately 20 days (no details given). The patients were evaluated as soon as the
1099 accident was discovered and started on Prussian blue. The adults received 3 g daily from
1100 days 35 to day 128 or 143. The children received 1, 1.5 or 2 g daily from days 35 to 86, 76
1101 or 99. The half-life of the caesium was very variable and was 124, 54, 61, 36 and 36 days
1102 without treatment. With Prussian blue treatment the half-life of caesium was 38, 39, 25, 17
1103 and 16 days, respectively (Ma et al., 1985).
1104
1105 12.1.4 Non-radioactive caesium
1106 A 65 year old woman presented to a hospital accident and emergency department with a one
1107 day history of recurrent fainting. The patient claimed to have essential hypertension and was
1108 having treatment for this from her family doctor. Six months prior to her presentation she
1109 had been diagnosed with rectal cancer and liver metastasis and she had experienced frequent
1110 episodes of watery diarrhoea in the past 4 weeks. On admission her blood pressure was
1111 138/55 mmHg, pulse 52/min regular, temperature 36.80C, respiratory rate 18/min and blood
1112 glucose 10.7 mmol/L. She developed and episode of Torsades de points (TDP) polymorphic
1113 ventricular tachycardia with transient loss of consciousness during initial assessment. The
1114 arrhythmia spontaneously converted back to normal sinus rhythm in about 10 seconds. Her
1115 electrocardiogram (ECG) showed QT prolongation with a corrected QT interval of 620 ms
24
1116 calculated by Bazetts formula. Serum electrolytes showed mild hypokalaemia (2.8mmol/L)
1117 whilst serum magnesium and serum calcium were normal. She was treated with intravenous
1118 magnesium sulphate and vigorous potassium replacement however there was no
1119 improvement in the QT prolongation after these therapies. At this stage it was discovered
1120 that in the previous 6 weeks the patient had been taking anticancer naturopathic drugs
1121 obtained from an alternative medical centre in Hong Kong. A detailed drug history was
1122 obtained. Her medications included methyldopa, Dologesic (dextropropoxyphene 32.5mg
1123 and paracetamol 325mg) and Lomotil (diphenoxylate 2.5mg, atropine 0.025mg) all
1124 prescribed by her family physician. In addition, a bottle of herbal powder (1 teaspoon taken
1125 daily), 3 oral medications including Gigamax (labelled as multivitamins), Slow K (slow
1126 release potassium supplement) and multi-C were prescribed by the naturopathic
1127 practitioner. On the basis of the clinical findings and along with previous case reports of
1128 caesium chloride use in anticancer therapy, the diagnosis of caesium poisoning was highly
1129 suspected. Whole blood and serum were assayed and the serum caesium concentration was
1130 elevated markedly at 288mol/L (normal range 0.0045-0.0105mol/L). Whole blood
1131 arsenic concentration was normal. One of the naturopathic medicines (multi-C) was found
1132 to contain 89% caesium chloride by weight. No undeclared contents or toxins were found
1133 on analysis of the herbal powder Gigamax and Slow K tablets. The patient was
1134 hospitalized for 2 weeks with intensive cardiac assessment and monitoring. The use of
1135 naturopathic medicines was stopped after hospitalization. Oral Prussian blue 3g 3 times
1136 daily was started on day 7 after hospital admission and continued for 4 weeks (day 7 to day
1137 34). Hypokalaemia was noticed during Prussian blue therapy and an oral potassium
1138 supplement was given to keep the serum potassium concentration at around 4mmol/L. Serial
1139 serum and urine caesium concentrations were measured. The calculated serum half-life of
1140 caesium was shortened from 61.7 days to 29.4 days with Prussian blue therapy. The
1141 corrected QT interval of her ECG returned to normal baseline on day 27 (Chan et al. 2009).
1142
1143 Thurgur et al. (2006) report a case where Prussian blue was used in the treatment of non-
1144 radioactive caesium. The patient was a 58 year old female with chronic caesium toxicity
1145 from the use of caesium chloride as an alternative cancer therapy. High levels of caesium are
1146 arrhythmogenic and this patient showed recurrent syncope, polymorphic ventricular
1147 tachycardia, hypokalaemia, and a QT prolongation of 690 ms. Along with conventional
1148 measures Prussian blue was used to treat her caesium toxicity. The Prussian blue treatment
1149 decreased the half-life of caesium from 86.6 days to 7.9 days, with associated normalization
1150 of QT interval and cardiac rhythm.
1151
1152
1153 12.2 Rubidium
1154 There are no reports on the use of Prussian blue in rubidium exposure in humans.
1155
1156 12.3 Thallium poisoning
1157 Reference values for thallium (Walker, 1998):
1158 Blood <5 nmol/L (<1 g/L)
1159 Urine <5 nmol/L (<1 g/L)
1160
1161 A 45 year old man with no significant medical history was hospitalized with peripheral
1162 neuropathy and paraesthesia of the extremities of all 4 limbs for 2 days. Clinical
1163 examination revealed an erythematous popular rash on the face and folliculitis on the lower
1164 limbs associated with hyperaesthesia of the feet and hands. An electromyogram showed
1165 severe polyneuropathy. The patient had a cardiac arrest 9 days after admission followed by
25
1166 post-anoxic coma. The patient worked in a technical crystals factory and handled thallium,
1167 bromide, caesium and iodide. The urinary thallium concentration measured twenty days
1168 after his cardiac arrest was 5118g/g of creatinine. Despite the late diagnosis treatment with
1169 insoluble Prussian blue (Radiogardase) was started 2 weeks later (42 days from his
1170 original admission to hospital) and continued for 24 days at a dose of 6g three times daily.
1171 Urinary thallium concentrations decreased from 1333g/g of creatinine to 166g/g of
1172 creatinine. After evaluation of the efficacy of the treatment a second course of Prussian blue
1173 therapy was started at 77 days post admission and continued for 1 month when the patient
1174 died. The urinary thallium concentration decreased from 86g/g of creatinine to 3g/g of
1175 creatinine (Villa et al., 2009).
1176
1177 Ten members of two families (family A and family B) sought treatment at a health care
1178 facility in Baghdad, Iraq. All patients were experiencing vomiting, abdominal pain and
1179 dysphagia. Over the next 4 days, 5 of the patients developed neurological signs and
1180 symptoms of varying severity (pain, abnormal sensations and weakness-particularly of the
1181 lower limbs). Four days after admission biological samples and a sample of a cake that all
1182 10 patients had consumed were submitted for toxicology testing. Thallium was detected in
1183 both the biological samples and the cake. On the eighth day after admission one of the
1184 patients, a child aged 11 years, died and two days later the 9 surviving patients were
1185 evacuated to Jordan for Prussian blue therapy which was not available in Iraq. A second
1186 patient, a 2 year old child died soon after arrival in Jordan, prior to receiving therapy.
1187 Prussian blue therapy was begun in the 8 surviving patients, now 11 days after they had
1188 eaten the cake. Two of these 8 patients were already comatose with severe cerebral oedema
1189 and subsequently died. Over the next thirty days, all 6 long-term survivors developed hair
1190 loss and 5 of the 6 survivors developed muscle weakness and spasticity of the lower limbs,
1191 with differing severity. An epidemiological investigation was started and it was discovered
1192 that the fathers of the two families were both board members of an Iraqi sporting club and
1193 had attended a routine board meeting on the day before hospital attendance in the clubs
1194 conference room. The cake, prepared by a local bakery and pre-divided into 10 pieces, had
1195 been delivered to the board meeting as a gift from a former board member. However the
1196 cake arrived late, after most board members had already left the meeting so no cake was
1197 eaten then. The two members that remained (the fathers of the two families) divided the
1198 cake and took the halves home to their families and it was eaten by both families at home
1199 that evening. Family A comprised seven members (parents and five children) and family B
1200 comprised five members (parents, two children and an uncle). Ten cases of abdominal pain,
1201 vomiting and dysphagia were identified among family members who consumed any amount
1202 of the cake. No other board members or their families were ill and no similar illnesses were
1203 reported at the health facility in Baghdad or at any nearby health facilities. Food exposure
1204 histories were collected in Jordan through interviews with family members. Ten people who
1205 ate portions of the cake became unwell; neither of the two persons who did not eat cake
1206 became unwell, however one of the two had tasted some of the cake icing and although
1207 asymptomatic, his blood and urine samples tested positive for thallium. A more rapid onset
1208 of illness occurred in adults and in persons who ate the most cake. Fatality was not
1209 significantly associated with sex, age, the amount of cake eaten, or the time to illness onset.
1210 Quantitative thallium levels were determined from blood and urine samples of nine patients
1211 taken on day 16 after eating the cake. Thallium was detected in all nine patients; the median
1212 blood thallium level was 289g/L (range 53-1,408 g/L; reference range expected <2g/L),
1213 and the median calculated 24 hour urine excretion of thallium was 3063 g/L (range 542-
1214 12,556 g/L; reference range expected <5g/L). Blood thallium levels correlated weakly
1215 with the amount of cake reported to have been eaten (CDC., 2008)
26
1216
1217 A previously healthy forty-year old male was admitted to hospital complaining of
1218 progressive weakness of his limbs, repeated vomiting and recurrent episodes of confusion.
1219 He had initially presented to the hospital six weeks previous to this admission complaining
1220 of thirst, nausea, vomiting, dizziness, parathaesias and arthralgias (predominantly of the
1221 lower limbs). The paraesthesias were not described as ascending or notably painful. A
1222 supine blood pressure of 180/90mmHg and a mild fever were the only physical findings
1223 noted. Neurological examination showed the cranial nerves to be intact and the results of
1224 muscle strength tendon reflex and cerebellar function tests were normal. There was no
1225 evidence of impaired superficial or position senses. The results of a complete blood cell
1226 count and blood chemistry tests were normal. He was discharged and symptomatic
1227 treatment (non-steroidal anti-inflammatory drugs) was prescribed. Two weeks before the
1228 present admission he returned complaining of general weakness, anxiety, myalgias
1229 (particularly of the legs), delayed growth of facial hair after shaving and thirst. Physical
1230 examination and routine laboratory tests were again normal. His symptoms were diagnosed
1231 as non-specific, partly attributed to stress. On his present final presentation he was alert
1232 and complained of double vision. Physical examination revealed hyperhidrosis, tachycardia
1233 (100beats/min) and supine blood pressure of 140/100 mmHg. Alopecia of the scalp was
1234 noted but eyebrows, eye lashes and body hair were intact. Neurological assessment
1235 disclosed horizontal and upbeat nystagmus, severe weakness of the lower extremities (more
1236 prominent proximally), bilateral absence of Achilles tendon reflexes, and lower limb ataxia.
1237 He did not complain of extreme pain and no objective signs of sensory changes were
1238 detected. He was found to have raised blood alanine aminotransferase and raised aspartate
1239 aminotransferase. There was no evidence of proteinuria. Lumbar tap revealed an elevated
1240 protein. Electroencephalogram showed persistent generalized slowing; the electromyogram
1241 displayed bilateral, severe, lower limb motor axonal neuropathy. Rapid deterioration of his
1242 neurological state was observed over the next few days, including flaccid paraparesis, lower
1243 limb areflexia, severe sensory impairment, mild distal arm and neck weakness, as well as
1244 occasional urinary and faecal incontinence. Visual disturbance progressed from impaired
1245 colour vision and decreased acuity to optic disc atrophy. Cognitive disturbances and
1246 hoarseness were also noted. Sural nerve biopsy showed early acute axonal degeneration
1247 with no evidence of vasculitis. At this stage he was started on intravenous immunoglobulin
1248 as a variant of Guillain-Barr syndrome (Milllar-Fisher type) could not be excluded, and
1249 alternative causes were explored. Several days later thallium poisoning was diagnosed as
1250 heavy metal urinalysis showed renal thallium excretion of 7mg/24 hours. Prussian blue was
1251 administered (250mg/kg/day, dissolved in 15% mannitol) daily through a nasogastric tube,
1252 along with forced diuresis. At this stage Mees lines appeared on his nail beds. No
1253 improvement in his general state was noted within the next two weeks. He became drowsy,
1254 required respiratory assistance and subsequently developed aspiration pneumonia. The
1255 suspicion of cardiotoxicity was raised by elevations of alanine aminotransferase, aspartate
1256 aminotransferase and creatine phosphokinase (MB fraction) levels however this was not
1257 substantiated by electrocardiographic follow-up and echocardiography. There was swelling
1258 and pain in his right knee, however, some clear fluid drained was inconsistent with any
1259 particular diagnosis. Rheumatoid factor was mildly elevated, without any other supporting
1260 evidence of concurrent arthritic disease. His condition stabilized over the next weeks and
1261 there was a gradual decrease in thallium urinary output (table below). He was transferred to
1262 a rehabilitation hospital after forty two days. A follow-up examination 3 months later the
1263 alopecia and Mees lines had completely resolved. There were no cognitive disturbances, his
1264 proximal strength was restored and his colour vision was normal. Decreased visual acuity
1265 and bilateral drop-foot were still evident however and the patient had only a vague
27
1266 recollection of his period in hospital.

1267
Daily excretion of thallium in urine
Hospitalization day Daily excretion (mg/day)
9 7
17 9
18 7.6
19 3.2
21 5.6
24 2.9
25 2.9
28 2.5
38 0
1268 (Atsmon et al., 2000)
1269
1270 A 67 year old woman was admitted to a county hospital because of acute pain in the chest,
1271 abdomen and lower limbs. The pain in the lower limbs was described as burning and severe.
1272 There was no vomiting or diarrhoea. The patient was discharged after 3 days with the cause
1273 of her illness undetermined. The patient then presented one week later to a private clinic
1274 because of persistent symptoms. Physical examination showed mild tenderness over the
1275 abdomen and electrocardiography showed non-specific T-wave inversion in the anterior
1276 waves. Routine urinalysis results were normal and laboratory tests showed normal blood
1277 cell counts, blood glucose level and kidney and liver function. The patient was treated
1278 symptomatically with analgesics. She was soon readmitted to hospital because of fainting
1279 spells and persistent symptoms. The patient suspected she was being poisoned. Paranoid
1280 psychosis and trichotillomania were diagnosed and she was admitted under restraint to the
1281 psychiatric department for observation. After being discharged home at week 5, the woman
1282 then re-presented at the private clinic. According to the patient the pain had become less
1283 severe. Physical examination showed diffuse alopecia which had started 2 weeks after the
1284 onset of the initial symptoms. Thallium poisoning was suspected. Urinalysis showed a
1285 thallium level of 8.56mol/L (normal level, 0.003mol/L; a level of 0.98mol/L is toxic).
1286 The case was reported to the police and the prime suspect was the patients 73 year old
1287 cohabitant. A dose of activated charcoal was given in the emergency department of a nearby
1288 district hospital and the patient was discharged home with a 2-week supply of succimer (2,
1289 3-dimercaptosuccinic acid) (no reason for this was given). At follow-up at week 6 however,
1290 it was found that the pain in her chest, abdomen and lower limbs had subsided, but
1291 symptoms of peripheral neuropathy had emerged - namely bilateral numbness and loss of
1292 exteroceptive and proprioceptive sensations in the toes. She had mild weakness in the
1293 proximal muscles of the lower limbs, as indicated by the patients difficulty in rising from
1294 the squatting position. She also complained of right-sided headache and tachycardia. She
1295 was immediately admitted to a University Medical Centre for treatment with oral Prussian
1296 blue (potassium ferric hexacyanoferrate) 4g every 8 hours. The blood thallium level at the
1297 time of hospitalization was 0.15mol/L. No other heavy metals were present. The patient
1298 tolerated Prussian blue very well, but hypoaesthesia developed over the medial aspect of her
1299 left calf on the second day of treatment. She was discharged 1 week later, when the urine
1300 level of thallium was 0.14mol/L. In week 9 the patient experienced neurological
1301 deterioration, impairment of short-term memory, double incontinence, tremor ataxia and
1302 falls. Physical examination showed hypoaesthesia of the right trigeminal nerve, general
1303 weakness of the extremities, cerebellar ataxia, tremor and dyskinesia. Plantar reflexes were
1304 normal and the urine thallium level was 0.33mol/L. By week fourteen the right facial
28
1305 numbness fully recovered, by week twenty there was recovery of sphincter control and
1306 regrowth of hair. Urine thallium was undetectable 2 weeks later. The weakness in the lower
1307 limbs, unsteady gait, falls and bruises persisted until 11 months after the initial presentation,
1308 when her condition improved noticeably although residual weakness continued (Pau., 2000)
1309
1310 A 24-year old female was admitted to hospital with a 4-month history of illness. Eight days
1311 after admission a diagnosis of thallium poisoning was made based on rapid diffuse alopecia,
1312 gastro-intestinal disturbance and a worsening neurological state combined with laboratory
1313 results. Whole blood thallium was measured and the first level was 300 g/L (normal
1314 <10g/L, toxic >100 g/L); the corresponding 24-hour urinary thallium value was 4300
1315 g/L (normal < 10 g/L, toxic > 200 g/L), consistent with severe intoxication. Colloidal
1316 soluble Prussian blue (KFe[Fe(CN)6]) was given orally at a dose of 250mg/kg/day in 2-4
1317 divided doses for 14 days. The patient also received mannitol as a cathartic, cisapride for
1318 her persistent constipation (started on the 5th day of treatment) and forced diuresis, which
1319 was achieved with furosemide, glucose, potassium and sodium chloride. The patients
1320 clinical course after treatment was uncomplicated with recovery of her vital signs within a
1321 week. Four months after treatment thallium was undetectable in a 24-hour assay. However
1322 after 6 months she still suffered from a lack of concentration and insomnia and never fully
1323 returned to her previous functional level. The source of thallium was never established
1324
Days before/after treatment 24 hour-urinary thallium Whole blood thallium level
level g/L g/L
-8 4300
0 4200 300
4 1450 < 10
10 330
14 468
18 440
31 260
1325 (Vrij et al., 1995).
1326
1327
1328 A thirty nine year old male with a history of heavy alcohol consumption became ill one
1329 week after returning from holiday in Spain. His symptoms started acutely with generalized
1330 pain and tingling all over his head and body and he was admitted to hospital where he was
1331 greatly distressed and complaining of shooting pains in his legs and back and leg weakness.
1332 It was thought initially that his illness was an alcoholic syndrome. Because of his continued
1333 deterioration despite multivitamin treatment he was transferred initially to the regional
1334 neurology unit and then further to an intensive care unit, 20 days after first becoming ill. On
1335 initial neurological examination he had respiratory distress, evidence of scalp hair loss, gaze
1336 evoked nystagmus in all directions, bilateral lower motor neuron, facial and bulbar
1337 weakness; his arms were minimally weak with normal reflexes but his legs showed a flaccid
1338 paralysis with absent reflexes. Initial biochemical investigations were within normal ranges
1339 (electrolytes, urea, creatinine and liver function tests). The electrophoresis pattern of serum
1340 proteins was normal and a non-specific auto-immune profile did not detect any auto-
1341 antibodies. Screening tests for abnormal urinary porphyrins gave negative results. A
1342 complete blood count was within the reference range, except for a slightly increased mean
1343 corpuscular volume. Cerebrospinal fluid was acellular with a protein count of 1.5g/L.
1344 Nerve conduction studies showed absent sensory and motor responses for the legs but
1345 normal values for the arms. On the basis of the clinical picture at this stage, in particular
29
1346 with respect to the hair loss, serum and urine were assayed for thallium and it was found to
1347 be present at toxic levels (value not stated). The patient deteriorated further and developed
1348 visual failure, complete external ophthalmoplegia, and total arreflexic paralysis of all limb
1349 and neck muscles. He was given two treatments of plasma exchange and treatment with
1350 potassium ferrihexacyanate (colloidal soluble Prussian blue), 5g every 6 hours by
1351 nasogastric tube was started (now thirty five days into the illness) and continued for 2
1352 months. At the same time intravenous potassium supplements (100-400mmol/day) were
1353 given. Excretion concentrations of thallium in serum and urine are tabulated below. The
1354 patient made a slow recovery which was complicated by septicaemia, recurrent
1355 supraventricular tachycardias and psychosis. He required 96 days of assisted ventilation and
1356 a total of 224 days in hospital. Some 500 days after the initial insult he still had a significant
1357 visual handicap, no fine finger function and could only walk a few steps with assistance.
1358 The source of the thallium poisoning was never discovered.
1359
1360
Excretion of thallium in serum
Hospitalization day Excretion (nmol/L)
28 914.4
46 54.8
48 25.4
49 19.0
55 8.8
56 6.9
57 6.9
58 7.5
59 6.3
60 7.4
1361
1362
Excretion of thallium in whole blood
Hospitalization day Excretion (nmol/L)
42 156.5
43 190.7
44 141.8
45 92.2
50 39.1
51 36.7
52 14.7
56 7.8
58 7.8
59 5.4
1363 Day zero = date of admission to hospital
1364 (Chandler et al., 1990)
1365
1366 Villanueva et al (1990) describe 5 cases of thallium poisoning in Spain. Four were members
1367 of a single family and the source of thallium was never ascertained. The fifth case was a
1368 female adult with a history of depression who intentionally ingested a thallium sulphate
1369 rodenticide. The family members (2 adults and two children aged 10 years and 3 years)
1370 presented initially with varying symptoms and the two children required admission to
30
1371 intensive care. Total hair loss of the 10-year old 2 weeks after admission led to the
1372 diagnosis of thallium poisoning. In all of the 5 cases urinary thallium was measured. The
1373 10 year old childs first measured thallium level was 18.4 mg/L, seven days later it was 5.8
1374 mg/L, at 27 days later it was 0.14 and by approximately 4 months it was 0.004 mg/L. The
1375 child had been treated with Prussian blue at a dose of 250mg/kg by duodenal tube
1376 administration every 6 hours until the urinary excretion of thallium was 0.5 mg/day. Her
1377 symptoms resolved in 20 days. The female adult who intentionally ingested the thallium had
1378 an initial urinary level of 2.4mg/L which decreased to 0.9mg/L in 4 days and to 0.1 mg/L in
1379 5 weeks. She had also been given Prussian blue at a dose of 250mg/kg/day (duration of
1380 treatment not stated) and 6 weeks later recovery was complete. The case reports also outline
1381 the thallium concentrations of the other family members but it is unclear whether or not they
1382 received Prussian blue therapy.
1383
1384 A 20-year-old chemistry student presented with a 3 day history of malaise and polyuria with
1385 paraesthesia of the fingers and lips. He had been using thallium and blood and urine
1386 analyses showed very high concentrations (5750 g/L and 60000 g/L, respectively),
1387 although he denied ingestion. Tests for thallium in hair samples were negative which
1388 excluded chronic ingestion however, despite exhaustive enquiries by the police and college
1389 authorities, the mode of thallium administration remained undetermined. Shortly after
1390 admission he became drowsy and had a convulsion. He developed progressive weakness
1391 over the next 12 hours, with severe pain in the calf muscles. He had peripheral and sensory
1392 impairment, dysarthria, dysphagia, paralytic ileus, tachycardia and ECG changes. He was
1393 started on soluble Prussian blue (5 g in 50 ml of 15% mannitol 4 times daily) and forced
1394 diuresis. On day 6 dialysis and haemofiltration were started and diethyldithiocarbamate was
1395 given. The diethyldithiocarbamate produced a short-lived increase in thallium excretion
1396 (from 17 to 142mg/24 h in urine, and 63 to 81mg/6 h dialysis) but also led to a rise in serum
1397 thallium concentration (from 800 to 1350 g/L and worsening neurological signs (including
1398 respiratory failure) and it was stopped. He required ventilation for 4 weeks. He developed
1399 almost complete alopecia before hair regrowth started. By 13 weeks he could swallow fluids
1400 and by 20 weeks he had normal upper limb function. But after 12 months he was still in a
1401 wheelchair owing to nerve damage to the lower limbs. Prussian blue and laxatives were the
1402 most effective means of enhancing thallium elimination, even though paralytic ileus caused
1403 long periods of constipation. High concentrations of thallium were present in the faeces up
1404 to day 18, and it was estimated that at least 2000 mg of thallium was excreted via this route
1405 in the first 20 days (see table). This is twice the quantity excreted by all the other methods
1406 in the same period. Forced diuresis was estimated to have eliminated 820 mg of thallium in
1407 46 days with 225 mg eliminated via haemodialysis in 25 days.
1408
No. of
days from Concentrations Excretion
admission
Serum Urine Urine Faeces Dialysate Urine
(g/L) (g/L) (mg) (mg) (mg) Filtrate
(mg)
1 5750 60000 129
2-5 2390 35900 398
6-10 680 7750 230 550 146 3.5
11-15 225 1520 42 155 64 1.0
16-20 35 640 12 1280 5.0 <0.1
21-25 15 280 2.6 0.5 5.4 <0.1
31
26-30 12 315 2.7 2.5 4.5 <0.1

31-40 11 110 2.9
41-50 <7 64 1.0
51-70 <7 24 0.9
Total quantities excreted (mg): 820 1990 225 4.5
1409
1410 The serum and urine concentrations presented in the table above are daily averages for the
1411 periods stated. The quantities excreted are totals for each period. All values are given as
1412 elemental thallium, measured by atomic absorption spectrometry (Wainwright et al., 1988).
1413
1414
1415 A group of 14 people ate dinner together and the following morning all complained of
1416 abdominal pain, vomiting and diarrhoea and were taken to hospital. Five of the 14 patients
1417 died in hospital within the next four days. The remaining nine patients (age range 16-70
1418 years) were seen over the following 4-7 days. One patient was pregnant, one had pre-
1419 existing Parkinsons disease and a third had elephantiasis of the legs. All of them
1420 complained of varying degrees of pain in the feet and legs and 6 were unable to walk. Some
1421 had headaches, constipation, abdominal pains, chest discomfort, loss of appetite, and loss of
1422 sleep. On examination they all had varying degrees of peripheral neuritis with
1423 hyperaesthesia, hyperalgesia, mental confusion, tachycardia, muscle and abdominal
1424 tenderness. A diagnosis of heavy metal poisoning was made based on the sudden onset of
1425 peripheral neuritis in a group of people who had eaten the same food and also because of
1426 similar case presentations in the previous year that had proven to be thallium poisoning.
1427 Blood and urine samples were sent for heavy metal analysis. Thallium was detected
1428 quantitatively in all the samples. The food they ate was suspected of being contaminated
1429 with a thallium-containing rodenticide but this could not be confirmed. Prussian blue was
1430 started between the 4th and 7th day at a dose of 2g three times a day orally, together with
1431 magnesium sulphate solution (30ml three times a day) to avoid constipation. For the first
1432 few days some of the patients required parenteral pethidine (100mg every six hours) for
1433 severe lower limb pain later changed to oral pentazocine (50mg three times a day). They
1434 were also given oral vitamin B complex and amiloride/hydrochlorothiazide daily. Over the
1435 next 5 days the leg pains rapidly subsided and analgesics were stopped. Seven of the
1436 patients started walking freely without much pain. In the 3rd week all of them gradually
1437 started losing scalp hair and there was almost complete alopecia after 4 weeks. Six patients
1438 developed Mee's lines on the finger nails along with hyperpigmentation over the knuckles.
1439 Four patients were discharged from hospital after the 4th week and the remaining patients
1440 after 6 weeks. Prussian blue was continued in all patients at the same dose for a total of 6
1441 weeks and no side effects were noted. On discharge 5 patients had fine tremor of the upper
1442 limbs with slight incoordination of movement. After sixteen weeks regrowth of scalp hair
1443 was complete. The pregnant woman had a premature delivery in the sixth month of
1444 pregnancy at another hospital but no details were available. By sixteen weeks all patients
1445 had returned to active life.
1446
Serum and urine thallium concentrations after two weeks of Prussian blue therapy
Patient number Patient age (years) Serum Thallium Urine Thallium
(gm/ml) (gm/ml)
1 62 16 2200
2 37 4 48
3 29 4 250
4 70 4 250
32
5 60 6 660
6 16 11 1100
7 29 5 37
8 30 6 87
9 26 4 23
1447 (Pai., 1987)
1448
1449 A 21-month old girl arrived at a hospital in the UK from Qatar for investigation of ataxia of
1450 five days duration. On admission she was semi-conscious and irritable but extensive
1451 investigations including routine toxicology screen on blood and urine, could only achieve a
1452 diagnosis of encephalopathy. On the 5th day of hospitalization hair loss was noted and a
1453 suggestion of thallium poisoning was made by a nurse in charge of the child (the subject of
1454 the crime thriller she was reading at the time, Agatha Christies A Pale horse). The child
1455 was treated with oral Prussian blue and potassium chloride (doses not stated) and after 3
1456 weeks of treatment there was marked clinical improvement and no thallium was detected in
1457 her urine. The clinical improvement continued and after four months the child was alert,
1458 ataxic but able to walk with help. The source of thallium was never determined but was
1459 thought to be the cockroach bait that was used in the home (Robb-Smith, 1987).
1460
1461 A 32 year-old woman was admitted to hospital 6 hours after allegedly ingesting 100mg of
1462 thallium sulphate. On admission the patient had malaise, nausea, vomiting and a burning
1463 retrosternal pain. After gastric lavage Prussian blue was administered 250mg/kg in divided
1464 doses) and combined haemoperfusion-haemodialysis (HP-HD) was started 7 hours after the
1465 alleged ingestion. HP-HD was instigated because the dose of thallium and whether there
1466 were possible co-ingestants were unknown. The patient was treated for 4 hours by HP-HD.
1467 Blood samples were taken before and after the charcoal column and after the artificial
1468 kidney at 1 hour intervals. Blood flow was 200ml/min. After HP-HD treatment 7 more
1469 blood samples were taken, initially at 1-hour intervals later at 2-hour intervals. During HP-
1470 HD treatment the patients blood pressure remained constant however there were frequent
1471 supraventricular extrasystoles. The patient improved and after 4 hours of HP-HD she felt
1472 well. Subsequent to her treatment no neurological or dermatological symptoms were noted.
1473 The combination of HP-HD in this patient obtained an overall clearance of 150ml/min in
1474 blood compared to 47ml/min (mean value) using HD only (De Backer et al., 1982).
1475
1476 A 28-year-old female presented 4 days after ingestion of nearly 1 g of thallium sulphate with
1477 lower abdominal pain, nausea, and hyperaesthesia of the limbs. Thallium was detected in
1478 the urine (3 mg/L) and gastric aspirate (10.8 mg/L). She was started on intravenous fluids
1479 and soluble Prussian blue (5 g four times daily via duodenal tube with 50 mL of 15%
1480 mannitol). Over the next two days the abdominal and lower limb pain persisted, with
1481 drowsiness and vomiting. On the third day she became hypotensive with bilateral ptosis.
1482 Alopecia was also noted. Neurological signs and gastrointestinal symptoms began to
1483 improve 4 days later, but hair loss continued. She had severe constipation for the first 6 days
1484 despite laxative administration. By 11 days her symptoms improved; Prussian blue was
1485 discontinued after 20 days, by which time hair regrowth had started. Thallium
1486 concentrations fell dramatically over the first 2 days of admission, with a slower decline
1487 thereafter (see table). No faecal samples could be obtained until the 10th day after poisoning
1488 (hospital day 6) owing to the severe constipation. At this time 1.6 mg of thallium was
1489 detected in the 24 hour faeces and 1.93 mg in the urine. In 28 days of hospitalization
1490 approximately 5 mg of thallium was eliminated via the intestinal tract and 35 mg in the
1491 urine. Approximately 55 mg was eliminated in the saliva between days 9 and 26 after
33
1492 poisoning. In total the quantity eliminated was thought to be <5% of the dose ingested. She
1493 was discharged asymptomatic at 28 days.
1494
Excretion of thallium (mg/day) in urine, faeces and saliva at various times during
hospital course
No. days after Urine (mg/day) Faeces (mg/day) Saliva (mg/day)
poisoning
4 5.68* Not determined Not determined
5-6 4.54 Not determined Not determined
7-9 2.26 Not determined 10.15
10-12 1.93 0.84 4.69
13-16 1.08 Not determined 2.03
17-22 0.27 0.41 0.38
23-26 0.25 0.02 0.18
1495 *Value calculated on 14 hour urine (Richelmi et al., 1980).
1496
1497 Comment: In the above case study the patients response to Prussian blue was slow to
1498 manifest and this may possibly have been due to her constipation. A very small amount of
1499 thallium was excreted in the faeces, and in fact, a very small amount was excreted overall so
1500 possibly the patient may have improved anyway regardless of therapy.
1501
1502 The efficacies of different therapies were evaluated in 18 cases of thallium poisoning treated
1503 between 1971 and 1979 at the University Hospital of Utrecht, the Netherlands. Patients
1504 were treated with gastric lavage if ingestion had occurred within the preceding 48 hours and
1505 then given 10 g soluble Prussian blue with 100 ml 15% mannitol via a duodenal tube twice
1506 daily. Eight patients were also treated with forced diuresis. Furosemide was given only if
1507 necessary to prevent fluid overload. Sixteen patients survived and two patients with cardio-
1508 vascular insufficiency died. The cases are summarized in the table below.
1509
Patient Sex Age Amount Time Thallium Treated Treated
of between concentra with with
thallium thallium tion in forced haemope
ingested ingestion urine on diuresis rfusion
(mg) - & admissio
from admissio n (mg/L)
patient n (days)
history
A F 21 500 28 2.1 - -
B1) F 22 2400 2 47.4 - -
C F 21 350 1 8.8 - -
D F 55 1000 4 20.2 - -
E M 23 1000 2 71.1 - -
F M 28 480 1.0 - -
G F 19 unknown 2 2.0 - -
H2) F 24 1000 1 84.0 - -
I F 32 1000 2 hours 40.0 - -
J M 45 unknown ? 3.0 - -
K M 50 750 4 24.6 + -
L M 26 875 1 54.0 + -
34
M M 21 1500 14 79.8 + -
N F 25 1500 1 80.0 + +
O3) M 44 unknown ? 8.0 + -
P3) M 19 unknown ? 10.0 + -
Q F 58 unknown 2 2.2 + -
R F 19 3000 1 50.0 + +
1510 1) Patient died after 4 days.
1511 2) The patient survived this suicide attempt. Four months later she died within 6 hours
1512 after ingestion of an unknown amount of thallium
1513 3) These patients were admitted with hair loss of the head
1514
1515 With soluble Prussian blue therapy, the mean half-life of thallium was 3.0 0.7 days. When
1516 administration of Prussian blue was combined with forced diuresis, the mean half-life of
1517 thallium was 2.0 0.3 days (van Kesteren et al., 1980).
1518
1519 An early report on the use of Prussian blue therapy in thallium poisoning reviewed 11
1520 patients hospitalized between 1971 and 1973. There were three men (aged 30 to 44 years),
1521 six women (aged 24 to 64 years) and two children (both female, aged 2 and 6 years). Three
1522 patients received Prussian blue by duodenal tube (2 x 10 g every two days, 2 x 10 g or 20 g
1523 daily). The other nine patients received oral Prussian blue (4 x 5 g daily in the adults, 4 x 1
1524 g daily in the 6-year-old and 4 x 1.7 g daily in the 2-year-old). Four patients treated within
1525 24 hours of ingestion of thallium did not develop any signs of toxicosis. Improvement also
1526 occurred in most of the other patients even though treatment was started late (between 9 and
1527 151 days after exposure). Thallium elimination was primarily via the faeces. Although no
1528 adverse effects were attributed to the Prussian blue therapy, one patient developed
1529 constipation and had constantly high blood thallium concentrations during the first few
1530 weeks of treatment (Stevens et al., 1974).
1531
1532
1533 A 26 year old female student, epileptic and treated with phenobarbital and phenytoin,
1534 ingested approximately 700mg of thallium sulphate when she was in a depressed mood. She
1535 ingested half of the amount during the evening and the remainder the following morning.
1536 She was admitted to hospital twelve hours later and was at this stage asymptomatic. On the
1537 third day hyperaesthesia of the legs and feet developed and she had abdominal discomfort.
1538 The next day (day 4) she developed a prickly, burning sensation in the feet and pain in the
1539 legs and shoulders. No other neurological symptoms could be demonstrated. The pain
1540 subsided during the subsequent days and then a slight polyneuropathy was found. Hair loss
1541 began on the tenth day and progressed but was not extreme. After two weeks only traces of
1542 neurological damage could be demonstrated and this disappeared during the following
1543 weeks. No Mees lines were seen on the nails. On initial admission to hospital, no thallium
1544 was evident after gastric lavage but it was shown to be present pharmacologically. She was
1545 treated with Prussian blue 250mg/kg body weight/day (given in 4 daily doses of 3.75g)
1546 along with 15% mannitol through a duodenal tube. Potassium chloride and activated
1547 charcoal were also given on the first two days. A multivitamin preparation was given
1548 intramuscularly 3 times a week and a fluid intake of 3-4 litres/day was prescribed. The
1549 decrease in urinary thallium concentration during the patients hospitalization is shown in
1550 the table below. Prussian blue was stopped on the 13th day when the amount of thallium in
1551 the urine was below 0.5 mg/24hours.
1552
1553
35

Hospitalization day Daily excretion (mg/24 hr)
2 13
6 5.1
8 1.4
13 0.5
1554 (Van der Merwe., 1972-Case study 1)
1555
1556 A twenty two year-old alcoholic ingested approximately 700 mg of thallous sulphate in a
1557 suicide attempt. He was admitted to hospital 6 hours later with no complaints. Gastric
1558 lavage showed only a trace of thallium. He was treated with Prussian blue 250mg/kg body
1559 weight in 15% mannitol via duodenal tube in 4 doses a day. Fluid intake of 3-4 litres a day
1560 was prescribed. After 4 days slight paraesthesia and sensory impairment of the toes could be
1561 demonstrated, however this improved and disappeared during the next few days. Hair loss
1562 started after 2 weeks but was mild. Thallium excretion in the urine is shown in the table
1563 below. Prussian blue treatment was stopped after the 10th day results were known.
1564
Hospitalization day Daily excretion (mg/24 hr)
2 3.3
3 3.4
5 1.8
10 0.2
1565 (Van der Meerwe., 1972-Case study 2)
1566
1567
1568 13. Summary of Evaluation

1569
1570 13.1 Indications
1571 Prussian blue is indicated in the treatment of patients with known or suspected internal
1572 contamination with radioactive caesium, radioactive thallium and non-radioactive thallium,
1573 to increase their rates of elimination. Treatment should be started as soon as possible after
1574 exposure.
1575
1576 13.1.1 Thallium
1577 The recommendation for the use of Prussian blue in thallium poisoning is based on evidence
1578 derived from animal studies and limited clinical data from human poisoning in the form of
1579 case reports and case series.
1580
1581 In animals experimentally poisoned with thallium, Prussian blue has been shown
1582 significantly to reduce absorption of thallium, increase its elimination and reduce its
1583 concentration in the brain. Moreover, Prussian blue significantly lowered mortality in
1584 animals poisoned by this metal.
1585
1586 Uncontrolled case reports / series have generally been associated with a favourable outcome,
1587 although there are some cases where patients were slow to respond to treatment and some
1588 patients have been left with long-term sequelae. In many of these cases other treatments
1589 were given concurrently (e.g. activated charcoal) and it is therefore difficult to clearly
36
1590 identify the benefits of Prussian blue alone.

1591
1592 Soluble Prussian blue has been shown to more than halve the elimination half-life, when
1593 compared to historical controls, in a large series of thallium poisoned patients. Although
1594 such extensive clinical documentation is not available for insoluble Prussian blue, the overall
1595 evaluation is that insoluble Prussian blue is also effective.
1596
1597 13.1.2 Caesium
1598 The recommendation to use Prussian blue in patients having ingested radioisotopes of
1599 caesium is based on its ability significantly to decrease absorption of, and increase the faecal
1600 excretion of, caesium in animals exposed to caesium-137. The body half-life was halved in
1601 the species tested and reduced content of caesium-134 in various organs was also
1602 documented. In healthy volunteers, insoluble Prussian blue more than halved the body half
1603 life of this radioisotope of caesium. The limited case studies available are consistent with
1604 the effect in healthy volunteers. There appears to be no data on the use of soluble Prussian
1605 blue in this situation.
1606
1607 13.2 Advised routes and dose
1608 Prussian blue should only be given orally. The manufacturers of the pharmaceutical
1609 preparation recommend the following doses (Heyl data sheets Radiogardase and Antidotum
1610 Thallii-Heyl, 2004):
1611
1612 Adults: In early-presenting cases when thallium or caesium may still remain in the gut an
1613 initial dose of 3g is suggested. In late-presenting cases when thallium or caesium have
1614 already been mostly absorbed, 3 to 20 g per day in divided doses should be given.
1615
1616 The individual dose should be based on the severity of exposure and clinical features.
1617
1618 Children 2 to 12 years: 1 g orally 3 times a day.
1619
1620 The efficacy and dosing for the paediatric population of insoluble Prussian blue has been
1621 extrapolated from adult data and supported by paediatric patients who were internally
1622 contaminated with cesium-137 and treated with Prussian blue in the Goinia incident.
1623 Paediatric patients aged 2-4 years are expected to have biliary and gastrointestinal function
1624 that is comparable with a 4-year old (Heyl, 2004).
1625
1626 Children less than 2 years
1627 The dosing regimen for children less than 2 years old has not been established although it
1628 has been used in this age group (Robb-Smith, 1987). Variations exist in the developmental
1629 maturity of the gastrointestinal and biliary systems of neonates and infants and the dose-
1630 related effects of Prussian blue on an immature gastrointestinal tract are unknown (Heyl,
1631 2004).
1632
1633 Administration
1634 The capsules of Prussian blue can be swallowed whole with liquid or if the patient is unable
1635 to swallow large numbers of capsules they can be opened and dispersed in bland food or
1636 fluid. A suspension of Prussian blue can also be administered via a stomach tube following
1637 gastric lavage.
1638
1639 In many patients with thallium poisoning mannitol (100 ml of 15% solution) has also been
37
1640 given with each dose in an effort to prevent constipation. This may not work and other
1641 measure to prevent or treat constipation may need to be undertaken.
1642
1643 End point of therapy
1644 The clinical end-point of Prussian blue therapy is generally considered to be when urinary
1645 thallium levels fall below 0.5mg/day (however this is clearly only a guide as most of the
1646 elimination will be faecal particularly in patients receiving Prussian blue therapy).
1647
1648
1649 13.3 Other consequential or supportive therapy
1650
1651 13.3.1 Caesium
1652 Specialist advice should be sought for the management of radiation accidents. This may require
1653 a multidisciplinary approach with radiation protection and dosimetry professionals, and medical
1654 and nursing staff trained and experienced in managing victims of radiation exposure
1655 (Breitenstein, 2003).
1656
1657 It is essential to prevent further incorporation of any radioactive material. Additional measures
1658 include the administration of laxatives to enhance gastrointestinal transit, antacids for
1659 radionuclides that become colloid or insoluble in the gastrointestinal tract (and therefore less
1660 absorbable), nasal and/or lung lavage and decontamination of skin and wounds (Gerber &
1661 Thomas, 1992).
1662
1663 In preliminary studies based on animal data, co-administration of Prussian blue with other radio-
1664 eliminators does not affect the efficacy of Prussian blue (Heyl, 2004; Kostail et al., 1983).
1665
1666 13.3.2 Thallium poisoning
1667 The treatment of thallium poisoning is primarily concerned with the prevention of absorption
1668 from the intestinal tract and enhanced elimination from the body.
1669
1670 Gastric lavage should be considered in patients who present early. As patients generally
1671 present to healthcare facilities many hours after exposure it is unlikely that lavage would be
1672 beneficial however gastric decontamination has been has been undertaken as late as 48 hours
1673 after thallium ingestion in some previous cases (van Kesteren et al, 1980). Many patients
1674 will also have vomited spontaneously by the time they attend hospital so as with gastric
1675 lavage, emesis should be considered but may not be of any benefit. Enhanced elimination is
1676 often required in severe cases and haemodialysis (Barckow & Jenss, 1976; Pederson et al.,
1677 1978), forced diuresis (Nogu et al., 1982; Heath et al., 1983; de Groot & van Heijst, 1988;
1678 Malbrain et al., 1997) and charcoal haemoperfusion (de Groot et al., 1985; van Kesteren et
1679 al., 1980) have all been used in thallium-poisoned patients.
1680
1681 13.4 Controversial issues and areas of use where there is insufficient information to
1682 make recommendations
1683
1684 13.4.1 Optimal form of Prussian blue
1685 Uncertainty exists in the historical literature regarding which of the two forms of Prussian
1686 blue (soluble or insoluble) is most effective as an antidote for radiocaesium and thallium.
1687 Human case study data is limited and this combined with the lack of analogous animal data
1688 on Prussian blue use (for both thallium and radiocaesium), means that whether the
1689 physicochemical differences between soluble and insoluble Prussian blue have any effect on
38
1690 outcomes in human poisoning is currently unknown. A relatively recent literature review by
1691 Thompson & Callen, (2004) highlights these controversies although they do conclude that
1692 that there is sufficient evidence to state that insoluble Prussian blue is effective in
1693 radiocaesium toxicity but that data are inconclusive for thallium.
1694
1695 From a pragmatic point of view, however, preference should be given to insoluble Prussian
1696 blue as this is the only commercially available pharmaceutical preparation.
1697
1698 13.4.2 Optimal dosage regimen
1699 The optimal dose of Prussian blue has not been established in clinical studies. The doses
1700 recommended by the manufacturer are empirical, reflecting the doses that have been used to
1701 treat cases of poisoning with thallium and radioactive caesium. In the case reports of
1702 poisoning with radioactive caesium the doses of Prussian blue used were smaller than those
1703 used for cases of thallium poisoning, typically 3g compared with 20g. Moreover, in one case
1704 series adults given doses of 3g, 6g and 10g per day showed very similar reductions in the
1705 half-life of caesium-137 (Lipsztein et al 1991). Since, however, the half-life of caesium-137
1706 was also found to be influenced by patient body weight and body burden of caesium-137
1707 interpretation of the impact of dosing is difficult.
1708
1709 In the case reports of poisoning with radioactive caesium, treatment was with insoluble
1710 Prussian blue, whereas for thallium poisoning treatment was often with the soluble form.
1711 Whether the form of Prussian blue has an impact on the effective dose for thallium poisoning
1712 is unknown.
1713
1714 Food may increase the effectiveness of insoluble Prussian blue by stimulating bile secretion
1715 and increasing enterohepatic circulation. The increase in enterohepatic circulation may
1716 increase the amount of caesium and thallium in the gastrointestinal lumen and hence
1717 increase the amounts available for binding with Prussian blue (Heyl, 2004).
1718
1719 13.5 Proposals for further studies
1720 In their review Thompson & Callen (2004) concluded that further research is needed to
1721 determine the significance of any differences between the two forms of Prussian blue and
1722 whether their physicochemical differences have any effect on outcomes in human poisoning.
1723
1724 Studies of the effect of Prussian blue in exposures to other radioisotopes may be warranted,
1725 e.g. in the case of rubidium-86. Although animal experiments suggest that Prussian blue may
1726 reduce the whole body retention of rubidium-86, the use of Prussian blue in this situation
1727 should be considered controversial.
1728
1729 13.6 Adverse effects
1730 Severe adverse effects have not been reported with Prussian blue (Hoffman, 2003). Mild to
1731 moderate constipation may occur which can be managed with a high fibre diet or bulk
1732 laxatives. In 46 patients involved in the Goinia incident treated with Prussian blue, 10
1733 developed constipation (Farina & Brando-Mello, 1991). It is essential to monitor for and
1734 treat constipation because elimination of thallium and caesium are dependent on the transit
1735 and elimination of Prussian blue from the gut. Faeces will be coloured blue and blue sweat
1736 and tears have been reported with prolonged administration, however this effect appears to
1737 be benign and transient (Hoffman, 2003). If capsules are opened and mixed with food or
1738 fluid, the teeth and mouth may be discoloured blue (Heyl, 2004).
1739
39
1740 Hypokalaemia is a potential risk as Prussian blue can bind potassium, however no significant
1741 variations in serum potassium concentrations have been reported, even when large doses
1742 have been given (IAEA, 1988). In 46 patients involved in the Goinia incident treated with
1743 Prussian blue there were only 3 cases of hypokalaemia (2.5 to 2.9 mmol/L) without clinical
1744 complications. Oral and intravenous potassium supplements resulted in prompt correction of
1745 hypokalaemia (Farina & Brando-Mello, 1991).
1746
1747 Cyanide toxicity has not been reported from oral dosing with Prussian blue.
1748
1749
1750 13.7 Restrictions for use
1751 None known. Prussian blue has been used in the treatment of thallium poisoning in
1752 pregnancy (Hoffman, 2000).
1753
1754
1755 14. Model Information Sheet

1756
1757 14.1 Uses
1758 Prussian blue (soluble or insoluble) is indicated
1759 for antidotal therapy in acute or chronic thallium poisoning,
1760 in the case of incorporation of radioisotopes of caesium (caesium-134, caesium-
1761 137),
1762
1763 14.2 Dosage and route
1764 Prussian blue is available as Radiogardase-Cs (Radiogardase in the United States of
1765 America) and Antidotum Thallii-Heyl distributed by Heyl Chemisch-pharmazeutische
1766 Fabrik GmbH, Berlin, Germany. Both products are available in bottles of 30 hard gelatine
1767 capsules, each containing 0.5 g of insoluble Prussian blue.
1768
1769 Prussian blue should only be given orally.
1770
1771 Adults and adolescents see comments above
1772 The recommended dose of Prussian blue is 3g orally three times/day
1773
1774 When the dose of radioactivity is substantially decreased the dose may be reduced to 1 or 2g
1775 three times/day to improve gastrointestinal tolerance
1776
1777 Paediatric dose (2-12 years)
1778 The recommended dose of Prussian blue is 1g orally 3 times/day
1779
1780 Neonates and infants
1781 Dose has not been established
1782
1783 In patients who cannot tolerate swallowing large numbers of capsules, the capsules may be
1784 mixed with bland food or liquids (this may result in blue discolouration of mouth and teeth).
1785
1786 Radiocaesium contamination: Treatment should be initiated as soon as possible after
1787 contamination is expected. Treatment should continue for a minimum of 30 days and then
1788 the patient should be reassessed for the amount of whole body radioactivity. The duration of
40
1789 treatment after exposure will be dictated by the level of contamination.

1790
1791 Thallium contamination: Ideally treatment should be initiated as soon as possible after
1792 exposure however Prussian blue is still thought to be effective after a delay in starting
1793 treatment and should not be withheld.
1794
1795 14.3 Precautions/contraindications
1796 As the antidotal effect of Prussian blue is due to the binding of thallium or caesium in the
1797 gut, it is only effective if the motility of the intestines is intact. In patients in coma or
1798 needing sedation, with reduced intestinal motility, medications to increase intestinal motility
1799 should be considered, although they are not proven effective in this setting.
1800
1801 Prussian blue decreases the duration of radiation exposure but does not treat the
1802 complications of radiation exposure. Supportive treatment for radiation toxicity symptoms
1803 should be given concomitantly with Prussian blue treatment.
1804
1805 In radiological emergencies the type of elemental exposure may not be known, Prussian blue
1806 may not bind to all the radioactive components and these elements may not undergo
1807 enterohepatic circulation which is necessary for Prussian blue binding and elimination. Thus
1808 patients contaminated with unknown or multiple radioactive elements may require additional
1809 treatments.
1810
1811 In severe thallium poisoning additional means for enhancing elimination should be
1812 considered; both charcoal haemoperfusion and haemodialysis have been used, although there
1813 are limited data to suggest that they have an impact on outcome. .
1814
1815 14.4 Pharmaceutical incompatibilities and drug interactions
1816 Prussian blue may bind oral drugs. When given together with oral tetracycline it is
1817 anecdotally reported to decrease the bioavailability of tetracycline.
1818
1819 Prussian blue may bind electrolytes in the gastrointestinal tract and asymptomatic
1820 hypokalaemia has occasionally been reported with its use.
1821
1822 14.5 Adverse effects
1823 Prussian blue is well tolerated; death or serious adverse effects have not been reported with
1824 Prussian blue. Mild to moderate constipation may occur which can be managed with a high
1825 fibre diet or bulk laxatives. It is essential to treat constipation as it will decrease elimination
1826 of thallium and caesium. Faeces will be coloured blue and blue sweat and tears have been
1827 reported with prolonged administration.
1828
1829 14.6 Use in pregnancy and lactation
1830 No contraindications. Prussian blue has been used in pregnant women and since it is not
1831 absorbed from the gastro-intestinal tract, effects on the fetus are not expected. The risk of
1832 toxicity from untreated radioactive caesium or thallium exposure is expected to be greater
1833 than the risk of reproductive toxicity from Prussian blue.
1834
1835 Prussian blue is unlikely to be excreted in breast milk as it is not significantly absorbed from
1836 the gastrointestinal tract, however, women with thallium toxicosis or exposure to
1837 radiocaesium should not breast feed due the risks to the baby from these elements.
1838
41
1839 14.7 Storage

1840 The pharmaceutical products of Prussian blue should be stored in the dark at 25 0C;
1841 occasional variations of temperature within the range 15 to 30 0C are permitted (Heyl, 2004).
1842
1843
1844 15. References

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2200
2201 Stevens W, van Peteghem C, Heyndrickx A & Barbier F (1974) Eleven cases of thallium
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2210
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2214
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2220
2221 Thurgar LD, Singh JM & Thompson MA (2006) Non radioactive caesium toxicity: A case
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2239
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2247
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2269
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2272 Med, 130(3): 953-956.
2273
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2275 Quantitative measurement of cyanide released from Prussian blue. Clinical Toxicology, 45:
2276 776-781.
2277
2278 Yang Y, Faustino PJ, Progar JJ, Brownell CR, Sadrieh N, May JC, Leutzinger E, Place DA,
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2281
2282 Walker AW (1998) SAS Trace Element Laboratories. Clinical and analytical handbook, 3rd
2283 edition. Guildford, Royal Surrey Hospital.
2284
2285
50
2286 16. Author(s) Name, Address

2287 Initial draft by ANP van Heijst, A von Dijk & J Ruprecht.
2288
2289 Update and revision by Maeve McParland, Paul Dargan, London
2290
2291 November 2009
2292
2293 17. Additional Information

2294
2295 Table 1: Results of EMBASE search 4th November 2009
Number Keywords Results
1 Prussian AND Blue 631
2 Thallium 7299
3 Caesium 959
4 Caesium 2718
5 Radiocesium 392
6 Poisoning OR 193447
Toxicity OR
Overdose
7 1 AND 2 47
8 Duplicate filtered: 1 47 unique results
AND 2 0 duplicate results
9 6 AND 7 33
10 1 AND 4 15
11 1 AND 5 14
12 1 AND 4 AND 6 1
13 1 AND 5 AND 6 4
14 Rubidium 1098
15 1 AND 15 0
2296
2297
2298 Table 2: Results of Medline search 4th November 2009
Number Keywords Results
1 Prussian AND Blue 860
2 Thallium 8122
3 Caesium 1138
4 Caesium 3733
5 Radiocesium 297
6 Poisoning OR 240196
Toxicity OR
Overdose
7 1 AND 2 49
Duplicate filtered: 1 49 unique results
AND 2 0 duplicate results
8 6 AND 7 32
9 1 AND 4 25
10 1 AND 5 14
11 1 AND 4 AND 6 3
51
12 1 AND 5 AND 6 4
14 Rubidium 1935
15 1 AND 14 0
2299 Results of Cochrane Library Search 4th November 2009

2300 No results found for Prussian blue using all possible MeSH terms.
52
Table 3: Summary of evidence of use of Prussian blue in metal poisoning
Metal Clinical trial data Case reports Animal studies
Radiocaesium No controlled trials Prussian blue treatment reduced Administration of a single dose
the half-life of caesium in 5 of radiocaesium and
Volunteer studies: patients accidentally exposed to concomitant oral dosing of
137
3 g daily of Prussian blue given Cs (Ma et al, 1985) Prussian blue resulted in
before 137Cs did not reduce reduction of caesium-uptake
caesium absorption. The Goinia incident Of 249 people from the gastrointestinal tract
increase in 137Cs excretion was contaminated with 137Cs, 46 were (Brenot & Rinaldi, 1967;
small following 0.5 g of treated with Prussian blue and this Dresow et al., 1990, 1993; Giese
Prussian blue three times daily significantly increased the rate of & Hantzch, 1970; Nielsen et al.,
(Madshus & Strmme, 1968). faecal excretion and reduced the 1988b; Nigrovi, 1963;
whole body burden retention of Nigrovi, 1965).
In 6 volunteers it was shown caesium (IAEA, 1988). In 15 of
that Prussian blue (4 x 0.5 g or these patients the body burden of The biological half-life was
10 x 0.2 g daily for 2-3 weeks) 137Cs was reduced by an average reduced (Madshus et al., 1966;
did not fully block caesium of 71% within 2 months of the Nigrovi et al., 1966; Havliek
uptake from contaminated food exposure (Melo et al, 1994). et al., 1967; Havliek, 1968;
(Volf et al., 1987). Mller et al., 1974; Richmond,
Comparing the elimination of 1968; Strmme, 1968).
137
Both forms of Prussian blue Cs from the bodies of 18 adults
were equally effective in after varying regimens of Prussian The reduced whole-body
reducing radiocaesium blue therapy, Lipsztein et al retention of caesium after
absorption in 2 male volunteers (1991) found that overall the half- treatment with Prussian blue was
who ingested meals labelled life of 137Cs was reduced by 32% seen in individual organs:
134
with a tracer dose of Cs, 10 and higher dose rates of Prussian muscle, bone, carcass, liver and
minutes after ingestion of 1 g of blue gave a greater reduction. kidney (Bozorgzadh, 1971;
Prussian blue (Dresow et al., Bozorgzadh & Catsch, 1972;
1993). Chernobyl incident Brenot & Rinaldi, 1967; Kostial
Fifteen students were exposed to et al., 1983; Mller et al., 1974;

134 137
In volunteer studies with 2 male Cs and Cs following the Stather, 1972; Wolsieffer et al.,
adults, the ingestion of Prussian Chernobyl accident. In 3 1969).
blue ten minutes before eating a volunteers the biological half-life
meal containing 134Cs reduced of caesium ranged from 42 to 71 In piglets soluble and insoluble
the caesium absorption more days. Insoluble Prussian blue was Prussian blue reduced the uptake
than the simultaneous admini- given from day 114 to 145 post- of 134Cs by more than 97%
stration of Prussian blue along exposure and this was reported to (Nielsen et al., 1988b).
with the labelled test meal. reduce the half-life of caesium
Administration of Prussian blue and enhance elimination (Tang et Prussian blue reduces the body
prior to the meal reduced al., 1988). content of 137Cs fed chronically
absorption of the radiocaesium to rats (Stather, 1972)
to 3-10% of the ingested dose
whereas simultaneous ingestion
of Prussian blue and the test
meal only reduced absorption to
38-63% (Nielsen et al., 1991).
In volunteer studies involving

self-dosing by the study
authors, ingestion of Prussian
blue 180 days after ingestion of
137
Cs reduced the biological
half-life of caesium from the
pre-treatment values of 110 and
115 days to 40 days (Madshus
et al., 1966).
In five cases where Prussian

blue was given several months
after caesium ingestion the
2

biological half-life of caesium
was reduced on average to one
third of its original half-life
(Madshus & Strmme, 1968;
Strmme, 1968).
A 37-year-old male was given

oral 137Cs followed by Prussian
the biological half-life of
caesium was reduced from 140
days to approximately 50 days
(Richmond, 1968).
Non-radiocaesium No controlled clinical trials Prussian blue therapy has been
reported to reduce the half-life of
non-radioactive caesium in two
separate case reports (Chan et al,
2009; Thurgar et al, 2009).
Rubidium No human data No Human data Prussian blue reduced the
biological half-time of retention
of Rubidium-86 in rats (Stather,
1972)
Thallium No volunteer studies. A total of 30 published reports of Concomitant oral administration
thallium poisoning treated with of thallium and of Prussian blue
Bhardwaj et al, 2006 (thallium- Prussian blue were found, in rats resulted in a lower uptake
201) studied the effect of involving 144 cases. These of the metal and lower
Prussian blue in 2 patients reports varied in terms of amount concentrations found in organs
following 201Tl myocardial of detail provided on treatment. In (Dvok, 1969; Heydlauf, 1969;
scintigraphy. In patient-1 whole addition there were a number of Rauws, 1974).
body radioactivity was reduced other variables that makes
by 18 and 30% after 24 and 48 comparison difficult. These Reduced retention and increased
3

hours, respectively, of oral reports are tabulated below. excretion of thallium by
Prussian blue therapy. Patient- Prussian blue results in a
2 developed constipation and There are single case reports: decrease of the thallium content
did not pass any stools after (Atsmon, 2000; Chandler 1990; in liver, kidney, skeleton, blood,
oral Prussian blue for 48 hours. DeBacker, 1982; Fred & Accad, heart and muscles (Dvok,
The whole body radiation 1997; Hologittas et al, 1980; 1969; Gnther, 1971; Heydlauf,
counts were similar to those Malbrain et al; Niehues et al 1969; Kravzov et al., 1993;
when Prussian blue was not 1995; Pau, 2000; Pedersen et al Manninen et al., 1976; Rauws,
given but there was a 1978; Richelmi, 1980; Rob-Smith, 1974; Ros et al., 1991; Ros &
concentration of radioactivity in 1987; Schwartz et al 1988; Monroy-Noyola, 1992; Sabbioni
the colon suggesting that the Stevens 1978; Villa et al, 2009; et al., 1982).
radioactivity was unavailable Vrij, 1995; Wainwright, 1988;
for resorption. Ros & Monroy-Noyola (1992)
and multiple case reports: demonstrated that Prussian blue
Van Kesteren, (1980) (CDC, 2008; Diaz et al 1990; increased LD50 of thallium by
retrospectively assessed the Ghezzi et al, 1979; Kamerbeek et 31%.
efficacy of different therapies al 1971; Meggs et al 1994; Moore
used in conjunction with et al 1993; Pai, 1987; Pelclova et Meggs et al (1997) found that
Prussian blue for thallium al 2009; Rangel-Guerra et al Prussian blue decreased the
poisoning in 18 patients. Two 1990; Stevens, 1974; Van mortality from thallium
patients died, and for the other Kesteren, 1980; Villanueva, 1990) poisoning in mice
16 mean half-life of thallium
was 3.0 0.7 days whilst when The extent and source of thallium In an evaluation of the effect of
Prussian blue was combined exposure is often unknown, Prussian blue in thallium-fed
with forced diuresis this was diagnosis delayed and hence a rats Lehman & Favari (1985)
reduced to 2.0 0.3 days delay in starting Prussian blue observed that whilst the control
therapy. Therapy was started group eliminated only 53% of
Kamerbeek et al, (1971) are within 24 hours in only 14 of the the administered thallium dose
credited with the first use of above reports (see case summary over the study period, the rats
Prussian blue in thallium table below). In other cases there that received Prussian blue
4

poisoning, demonstrating an were varying delays: Villa et al, eliminated 82% of the dose.
approximately 7-fold increase (2009) - 42 days; CDC, (2008) - 8
in faecal elimination with its days; Atsmon, (2000) -10-11 Kamerbeek, (Kamerbeek, 1971;
use. weeks; Pau, (2000) - 6 weeks; Kamerbeek et al., 1971) showed
Vrij, (1995)> 4 months; Chandler that after four days of Prussian
A reduction in thallium half-life (1990) - 35 days; Villanueva, blue therapy the concentration of
was observed in thallium (1990) > 2 weeks; Wainwright, thallium in the brain of the
poisoned patients when (1988) approx. 5 days; Pai, (1987) treated groups was less than half
compared with no therapy at all - 4 to 7 days; Rob-Smith, (1987) - that of the control group. The
(De Groot & van Heijst, 1988) 5 days. muscle thallium concentration in
the treated group was almost
Dosing patterns for Prussian blue one-fourth of that of the control
varied from case to case (amount and a dose dependent
given and duration of treatment) relationship was determined.
as did use of concomitant therapy.
(Gnther, 1971) demonstrated
From the limited case studies that soluble Prussian blue
Prussian blue appears to be well increased excretion of thallium
tolerated and reported to be in rats and reduced the LD50
effective in enhancing the however only if started within
excretion of thallium. 24 hours of exposure.
Constipation is reported in earlier
case studies (Wainwright, 1988;
Richelmi, 1980), less so in later
cases however many have given
mannitol along with the Prussian
blue.
5
Table 4: Summarized case reports of thallium poisoning (NB - please complete the table where there are "?" if you have access to the full papers)
Author No cases Amount thallium Thallium level on Interval Form of PB Dosing Other treatments Outcome
presentation between regimen
onset of
illness and
treatment
Villa et al 1 NK Urine: 5118 g/g 42 days Insoluble 6g tds Died (final Tl
2009 creatinine (18g/day) for level 3 g/g
24 d, second creatinine
course for 31d
Atsmon et al 1 NK Renal excretion >9 days ? 250 mg/kg/d mannitol Neurological
2000 7mg/24 hours sequelae
Pau, 2000 1 Urine at 35d: 8.56 ~42 days Colloidal 4g every 8 Activated charcoal, Persistent
mol/L (NR = soluble hours Succimer, weakness
0.003 mol/L) (12g/day)
Blood at 42d: 0.15

mol/L (NR <0.07
mol/L)
Vrij et al 1995 1 NK Urine (24 hr): 4300 ~128 days Colloidal 250 mg/kg per Mannitol, cisapride, Neurological
g/L soluble day for 14 forced diuresis sequelae
(NR <10 g/L) days
Blood: 300 g/L

(NR <10 g/L)
Malbrain et al 1 8.75g thallium Urine: 69,600 g/L 2 hours Colloidal 3g then 0.5g Emesis & gastric lavage Neurological
1997 sulphate soluble 6xday Mannitol, lactulose sequelae
Blood: 5,240 g/L (3g/day) for Potassium,
20 days haemodialysis
Chandler 1 NK 35 days Colloidal 5g every 6 hrs Plasma exchange, i.v. Neurological

1990 soluble (20g/day) for potassium, sequelae
2 mths
Wainwright et 1 NK Urine: 6000 g/L 3 days Colloidal 5g every 6 hrs Mannitol, forced Neurological
6
onset of
illness and
treatment
al 1988 soluble (20g/day) diuresis, haemodialysis, sequelae
Blood 5750 g/L haemofiltration, (estimated faecal
diethyldithiocarbamate excretion of Tl
2g over 20d; by
forced diuresis
820mg; by
dialysis 225mg)
Robb-Smith 1 (21 mth NK ? >10 days ? NK, for 3 Potassium Neurological
1987 child) weeks sequelae
De Backer et 1 100 mg thallium Blood: 415 g/L 6 hours Colloidal 250mg/kg Gastric lavage, Recovered
al 1982 sulphate soluble (per day?) combined
haemoperfusion-
haemodialysis for 4 hrs
Richelmi et al 1 1 g thallium sulphate Urine: 3000 g/L 4 days Colloidal 5g every 6 Mannitol Recovered
1980 soluble hours
Gastric aspirate: (20g/day) for
10800 g/L 20 days
Fred & Accad 1 ? ? ? ? ? ? ?
1997
Hologgitas et 1 ? ? ? ? ? Kayexelate (sodium died
al 180 polystyrene)
Niehues et al 1 (2 NK Urine: 9000 g/L 0.5 hours ? 0.5 mg (sic Gastric
1995 admissions) 2nd adm.: 3700 g/L NK /day for 6 decontamination
days Haemodialysis
2nd adm: aemodialysis,

Same dose forced diuresis (1 l
urine/h), orthograde
intestinal infusions,
potassium
Nogue et al 1 750 mg thallium Blood: 950 g/L >1.5 days Not stated 1g 8 hourly Mannitol
7
onset of
illness and
treatment
1982 sulphate (approx) (30g/day) Forced diuresis with
days 1-4 and potassium
16-19 Haemodialysis
IV and oral Diethyl
dithiocarbamate
Oral
Diphenylthiocarbazone
(dithizone)
Pedersen et al 1 2g ? ? ? ? Forced diuresis

1978 haemodialysis
Schwartz et al 1 ? ? ? ? ? ? ?
1988
Stevens 1978 1 ? ? ? ? ? ? recovered
CDC 2008 10 (5 NK Blood: 289 g/L 11 days Insoluble 250 mg/kg/d 2 children died
children) (median); range 53 - (Antidotum- before treatment;
1408 g/L Thallii-Heyl & 2 adults died
Radiogardase) (already
Urine (24hr): 3063 comatose before
g/L (median); treatment started)
range 542 - 12556
g/L
De Groot et al Case 1 NK Blood 2800 g/L <48 hrs Not stated 10g twice per Gastric lavage Recovered
1985 day Mannitol
Case 2 NK Blood 5800 g/L Forced diuresis Recovered
Case 3 NK Blood 1900 g/L Haemoperfusion Recovered
Daz et al Case 1 NK Urine: 11400 g/L 5 days Not stated 12 days Magnesium sulphate, Recovered
1990 potassium, furosemide,
Case 2 NK Urine: 6300 g/L 12 days Not stated Potassium Recovered
Diuretics
8
onset of
illness and
treatment
Case 3 NK Urine: 3500 g/L 7 days Not stated Magnesium sulphate, Recovered
potassium, furosemide,
Case 4 15 mg Urine: 3090 g/L 15 days Not stated Not stated Potassium Recovered
Diuretics Note: 6000g/L
thallium level at
45 days after
intoxication. No
new ingestion of
thallium
reported.
Villanueva et 4 (2 NK 10yr old: 18400 >14 days ? 250mg/kg 6 Recovery

al 1990 children) g/L hourly
1 adult NK 2400 g/L 250 mg/kg/d Recovery
Van der Case 1 700 mg thallium 12 hrs ? 250 mg/kg/d Activated charcoal Recovered?
Merwe 1972 sulphate (4 x Mannitol
3.75g/day) for Potassium
13 days Multivitamins
High fluid intake
Case 2 700 mg thallium >6 hours ? 250 Gastric lavage Recovered?
sulphate mg/kg/day in Mannitol
4 doses for 10 High fluid intake
days
Pai 1987 14 4-7 days Colloidal 2g every 8 hrs Magnesium sulphate, 5 died before
Case 1 NK Urine 2200 g/mL soluble (6g/day) for 6 analgesia, diuretics, treatment
(sic) weeks vitamin B complex 9 recovered
Blood 16 g/mL
(sic)
Case 2 Urine 48 g/mL
9
onset of
illness and
treatment
(sic)
Blood 4 g/mL (sic)
(sic)
Blood 4 g/mL (sic)
(sic)
Blood 4 g/mL (sic)
(sic)
Blood 6 g/mL (sic)
(sic)
Blood 11 g/mL
(sic)
(sic)
Blood 5 g/mL (sic)
(sic)
Blood 6 g/mL (sic)
(sic)
Blood 4 g/mL (sic)
Van Kesteren 18 (details Urine concentration Colloidal 10g twice per
et al 1980 below): (mg/L) soluble day (20g/day)
A 500 mg 2.1 28 days
B 2.4 g 47.4 2 days Gastric lavage Died
C 350 mg 8.8 1 day Gastric lavage
D 1g 20.2 4 days
E 1g 71.1 2 days Gastric lavage
10
onset of
illness and
treatment
F 480 mg 1.0 day Gastric lavage
G unknown 2.0 2 days Gastric lavage
H 1g 84.0 1 days Gastric lavage Survived but
died 6hrs after
second overdose
with thallium
I 1g 40.0 2 hours Gastric lavage
J unknown 3.0 ?
K 750 mg 24.6 4 days Forced diuresis
L 875 mg 54.0 1 day Gastric lavage, Forced
diuresis
M 1.5 g 79.8 14 days Forced diuresis
N 1.5 g 80.0 1 day Gastric lavage
Forced diuresis,
haemoperfusion
O unknown 8.0 ? Forced diuresis
P unknown 10.0 ? Forced diuresis
Q unknown 2.2 2 days Gastric lavage
Forced diuresis
R 3g 50.0 1 Gastric lavage
Forced diuresis,
haemoperfusion
Stevens et al Case 1 NK Urine 1430 g/L 30 days Not stated 10g twice per Activated charcoal Recovered with
1974 day every 2 Potassium some muscular
days. Duration weakness at 3
not stated mth
Case 2 1000mg Not stated Few hours 10g twice per Gastric lavage Recovered
day every 2
days for 11
days
Case 3 NK Urine: 7100 g/L 42 days 20g per day Neurological
11
onset of
illness and
treatment
for 15 days sequelae
Case 4 300 mg Urine elimination 10 hours 5g four times Gastric lavage Recovered
3220 g/24 hrs per day for 19 mannitol
days
Case 5 NK Urine elimination 94 days 5g four times mannitol Neurological
120 g/24 hrs per day. sequelae
Duration not
stated
Case 6 NK Urine 570 g/L 28 days 5g four times mannitol Recovered
per day for
>50 days
Case 7 NK Urine 232 g/L 62 days 5g four times mannitol Recovered
2nd admission: urine per day for 18
230 g/L days
Case 8 NK Not stated 151 days 5g four times Mannitol, Recovered

per day for 45 Potassium, antibiotics
days
Case 9 300 mg Urine elimination 2 hours 5g four times Gastric lavage Recovered
2310 g/24 hrs per day for 25 Potassium
days
Case 10 225 mg Urine elimination 9 days 1g four times mannitol Recovered
(child 6yrs) 840 g/24 hrs per day for 35
days
Case 11 NK Urine elimination 1 day 1.7g four Lactulose, furosemide Recovered
(child 2yrs) 180 g/24 hrs times
Ghezzi & 5 (1 ? ? ? ? ? Dithizone (1 patient) Died
Bozza neonate) 4 recovered
Marrubini,
1979
Kamerbeek et Case 1 400 mg Not stated Not stated Colloidal ? ? ?
12
onset of
illness and
treatment
al 1971 soluble?
Case 2 400 mg Not stated Not stated Colloidal
soluble?
Case 3 2000 mg Not stated 14 days Colloidal
soluble?
Meggs et al 4 NK Urine: 10837 g/L 2 days ? 2g tds Multiple dose activated Recovered
1994 and 9569 g/L (6g/day) charcoal,
haemodialysis,
analgesia
Moore et al 2 NK Blood: 600 g/L >28 days Colloidal 250 mg/kg/d sequelae
1993 (approx) soluble
Pelclova et al Case 1 NK Urine: 8.5 g/L NK - had Insoluble 6g per day for Neurological
2009 Blood 0.3 g/L probably be 5 days sequelae
poisoned
several times
over 2 years
Case 2 NK Urine: 2800 g/L 4 weeks Insoluble 6g per day for Neurological
Blood: 770 g/L approx 21 days sequelae
Rangel- 50 NK Ranges: Not stated Colloidal 3g/day for 10- Gastric lavage 1 death
Guerra et al Urine 100 - 28000 soluble? 14 days Forced diuresis
1990 g/L 3 patients also received
Blood: 100 - 1360 sodium iodide,
g/L 5 patients also received
potassium iodide
Case 1 NK Urine: 420 g/L 4 weeks Colloidal 3 g/day? Forced diuresis, Recovered
soluble? painkillers
Case 2 NK placental exposure Urine: 60 g/L 14 days Colloidal Not stated Not stated Neurological
(neonate soluble? sequelae
from Case
1)
13
onset of
illness and
treatment
Case 45 NK Urine: 950 g/L 2 months Insoluble 3 g/day? Not stated Neurological
sequelae
14

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11 Potassium ferric (III) hexacyanoferrate (II) (colloidal soluble Prussian Blue,

86 2. Name and Chemical Formula of Antidote

Potassium ferric (III) Ferric (III) hexacyanoferrate (II)

122 3. Physico-chemical Properties

124 Melting point: Not available.

166 4. Synthesis and Pharmaceutical Formulation

173 FeCl3 + K4[Fe(CN)6] ------ > KFe[Fe(CN)6] + 3 KCl

235 5. Analytical Methods

272 Thallii-Heyl and Radiogardase-Cs do not contain oxalic acid.

322 detected using gamma spectrometry.

347 7. General Properties

421 8. In Vitro Studies

485 9. Animal Studies

718 Manninen et al, 1976; Rauws, 1974).

768 Purkinje cells (Barroso-Moguel et al, 1994).

929 10. Volunteer Studies

1017 11. Clinical Studies Clinical Trials

1023 12. Clinical Studies - Case Reports

1266 recollection of his period in hospital.

26-30 12 315 2.7 2.5 4.5 <0.1

Daily excretion of thallium in urine

1568 13. Summary of Evaluation

1590 identify the benefits of Prussian blue alone.

1755 14. Model Information Sheet

1789 treatment after exposure will be dictated by the level of contamination.

1839 14.7 Storage

1844 15. References

1888 Thallium intoxication treated with combined hemoperfusion-hemodialysis. J Toxicol Clin

1938 Lyon RC (2008) Quantitative determination of caesium binding to ferric hexacyanoferrate:

2238 An evaluation of therapy. Intensivmed, 17: 293-297.

2286 16. Author(s) Name, Address

2293 17. Additional Information

2299 Results of Cochrane Library Search 4th November 2009

Metal Clinical trial data Case reports Animal studies

In volunteer studies involving

In five cases where Prussian

Metal Clinical trial data Case reports Animal studies

A 37-year-old male was given

Metal Clinical trial data Case reports Animal studies

Metal Clinical trial data Case reports Animal studies

Blood at 42d: 0.15

Blood: 300 g/L

Chandler 1 NK 35 days Colloidal 5g every 6 hrs Plasma exchange, i.v. Neurological

2nd adm: aemodialysis,

Pedersen et al 1 2g ? ? ? ? Forced diuresis

Villanueva et 4 (2 NK 10yr old: 18400 >14 days ? 250mg/kg 6 Recovery

1 adult NK 2400 g/L 250 mg/kg/d Recovery

Case 8 NK Not stated 151 days 5g four times Mannitol, Recovered

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